Prevention of cellular senescence in mammals by natural peptide complexes

ABSTRACT

Preventing skin aging by targeting multiple causes by a single bullet is of primal scientific and consumer interest. A treatment based on compositions of compound (I) for cellular senescence to control cellular degradation offers such a solution to multiple skin ailments including skin degradation from cancer, diabetes, radiation treatments, chemotherapy, and sun-burn; mitochondrial dysfunction, age spots, acne, loss of cellular antioxidants, collagen loss, loss of skin pliability, loss of skin suppleness, skin wrinkles including fine lines, oxidation, damage from radiation, damage from free radicals, damage from UV, dry skin, xerosis, ichthyosis, dandruff, brownish spots, keratoses, melasma, lentigines, liver spots, pigmented spots, dark circles under the eyes, skin pigmentation including darkened skin, blemishes, oily skin, warts, eczema, pruritic skin, psoriasis, inflammatory dermatoses, topical inflammation, disturbed keratinization, skin changes associated with aging, scalp dryness, skin depigmentation, intracellular dehydration, and combinations thereof;

This invention is a continuation-in-part of U.S. patent application Ser.No. 11/309,437 (filed Aug. 4, 2006), now U.S. Pat. No. 7,427,690; andU.S. patent application Ser. No. 13/015,805 (filed Jan. 28, 2011).

BACKGROUND OF THE INVENTION

Cells are the fundamental structure composing our bodies, and cellulardecline thus contributes to the aging process. Senescence or biologicalaging is the change in the biology of an organism as it ages after itsmaturity. Such changes range from those affecting its cells and theirfunction to that of the whole organism.

This invention relates to certain amides of amino acids, peptides, andamino sugars. The compounds of the present invention possess cellularanti-senescence properties, which are suitable for topical or oralapplication for the treatment of ailments related to cell degradationcaused by such cellular senescence, which include acne, rosacea, topicalwounds, dandruff, skin disfigurements, age spots, wrinkles and finelines, excess facial oil, and veterinary problems that result fromintra-cellular dehydration and concomitant onset of intra-cellularinflammation including activation/inactivation of matrixmetalloproteases (MMP), tyrosinase, proteasomes, and other enzymes inmammals.

DESCRIPTION OF THE RELATED ART

Wang et al. (FEBS Lett. 2011 Apr. 6; 585(7):986-94) report ageing inmammals remains an unsolved mystery. Anti-ageing is a recurring topic inthe history of scientific research. Lifespan extension evoked by Sir2(Silent information regulator S2) protein in lower organisms hasattracted a large amount of interests in the last decade. They reviewrecent evidence supporting the role of a Sir2 mammalian homologue, SIRT1(Silent information regulator T1), in regulating ageing and cellularsenescence. The various signaling networks responsible for theanti-ageing and anti-senescence activity of SIRT1 have been discussed.In particular, a counter-balancing model involving the cross talksbetween SIRT1 and AMP-activated protein kinase (AMPK), another stressand energy sensor, is suggested for controlling the senescence programin mammalian cells.

Lo et al. (Cell Transplant. 2010 Nov. 5) report glucose reductionprevents replicative senescence and increases mitochondrial respirationin human mesenchymal stem cells.

Zhou et al., (Atherosclerosis, 2010 November; 213(1):92-101) disclosethat angiotensin II (Ang II) is able to accelerate endothelialprogenitor cells (EPCs) senescence through induction of oxidativestress. Calcitonin gene-related peptide (CGRP), a major neurotransmitterof the capsaicin-sensitive sensory nerves, protects endothelial functionthrough down regulating the expression of NADPH oxidase and reactiveoxygen species production and increasing the production of klotho.

Campaner et al., (Cell Cycle. 2010 Sep. 15; 9(18):3655-61) disclose Rasproteins induce senescence, while Myc proteins generally triggerapoptosis. Myc is in fact viewed as an anti-senescence oncogene, as itis a potent inducer of cell proliferation and immortalization, bypassesgrowth-inhibitory signals, and cooperates with Ras in cellulartransformation.

Zhong et al. (Diabetes Res Clin Pract. 2010 July; 89(1):38-45 reportendothelial dysfunction to be a key event in the onset and progressionof atherosclerosis associated with diabetes. Increasing cell senescencemay lead to endothelial dysfunction and contribute to vascularcomplications. L-arginine may have an anti-senescence effect and itmight be a therapeutic agent for diabetic vascular complications.

Xie et al. (Pharmazie. 2009 November; 64(11):752-4) report effects ofechinacoside, one of the phenylethanoids isolated from the stems ofCistanches salsa, a Chinese traditional herbal medicine, on human embryolung fibroblastic cells. The results indicate that echinacoside couldprotect cells from DNA damage, suggesting that echinacoside haspotential anti-senescence activity.

Zin et al., (Pharmazie. 2008 April; 63(4):321-3) studied the influenceof dendroflorin, a potentially active compound extracted from Dendrobiumnobile, on cell growth and cell cycles was assessed in a human embryolung fibroblastic cell; the results suggest that dendroflorin is apotential candidate with anti-senescence activity.

Ikushima et al., (Biochem Biophys Res Commun. 2006 Jan. 20;339(3):827-32) report Klotho-mutated mice manifest multiple age-relateddisorders that are observed in humans. A recent study suggested thatKlotho protein might function as an anti-aging hormone in mammals.Klotho acts as a humoral factor to reduce H₂O₂-induced apoptosis andcellular senescence in vascular cells.

Afanasev (Oxid Med Cell Longev. 2010 March-April; 3(2):77-85) reportsreactive oxygen species (ROS) superoxide and hydrogen peroxide performimportant signaling functions in many physiological andpathophysiological processes. Cell senescence and organismal age are notexemptions. Aging-regulating genes p66shc, Sirtuin, FOXO3a and Klothoare new important factors which are stimulated by ROS signaling. It hasbeen shown that ROS participate in initiation and prolongation ofgene-dependent aging development. ROS also participate in the activationof protein kinases and extracellular signal-regulated kinase ERK, whichby themselves or through gene activation stimulates or retards cellsenescence. Different retarding/stimulating effects of ROS might dependon the nature of signaling species—superoxide or hydrogen peroxide.Importance of radical anion superoxide as a signaling moleculewith“super-nucleophilic” properties points to the possibility of the useof superoxide scavengers (SOD mimetics, ubiquinones and flavonoids) forretarding the development of aging.

Lester (Plant Sci. 2000 Dec. 7; 160(1):105-112) reports activated oxygenfree-radicals cause peroxidative damage to all membranes and hastensenescence. Polyamines (PAs) are effective scavengers of these freeradicals produced by lipoxygenase and phospholipase-D.

Wang et al., (Biochemistry (Mosc). 2000 July; 65(7):869-71) reportCarnosine is an endogenous free-radical scavenger. The latest researchhas indicated that apart from the function of protecting cells fromoxidation-induced stress damage, carnosine appears to be able to extendthe lifespan of cultured cells, rejuvenate senescent cells, inhibit thetoxic effects of amyloid peptide (A beta), malondialdehyde, andhypochlorite to cells, inhibit glycosylation of proteins and protein-DNAand protein-protein cross-linking, and maintain cellular homeostasis.Also, carnosine seems to delay the impairment of eyesight with aging,effectively preventing and treating senile cataract and otherage-related diseases. Therefore, carnosine may be applied to human beingas a drug against aging.

Certain amides of amino acids and peptides have been reported to possessinteresting biological properties. Notable examples follow.

Conjugates of certain amino acid amides have been disclosed to possesstyrosinase inhibitory benefits (Jin-mi Noh et al., Bioorganic &Medicinal Chemistry Letters, Volume 19, Issue 19, 1 Oct. 2009, Pages5586-5589).

Monoterpene-based chiral β-amino acid derivatives have been preparedfrom natural sources (Szakonyi et al., Amino Acids. 2011 Mar. 30).

Bertinaria et al., (J Med. Chem. 2011 Jan. 27; 54(2):611-21), disclosesynthesis and the physicochemical and biological characterization of aseries of carnosine amides bearing on the amido group alkyl substituentsendowed with different lipophilicity are described. All synthesizedproducts display carnosine-like properties differentiating from the leadfor their high serum stability.

Ueoka et al., (J Am Chem. Soc. 2010 Dec. 22; 132(50):17692-4), disclosetwo cytotoxic peptides, yaku'amides A and B that were isolated from themarine sponge Ceratopsion sp. The growth inhibitory profile ofyaku'amide A against a panel of 39 human cancer cell lines was clearlyunique and distinguished from other anticancer drugs.

Acharya et al., (J Biomed Sci. 2010 Aug. 24; 17 Suppl 1:S35), reportthat when used in overdoses, acetaminophen (APAP) is a common cause ofmorbidity and mortality in humans. At present, N-acetylcysteine (NAC) isthe antidote of choice for acetaminophen overdoses. Promptadministration of NAC can prevent the deleterious actions of APAP in theliver. In view of the similarities in antioxidant effects demonstratedby NAC, hypotaurine (HYTAU) and taurine (TAU) in this and other ourlaboratories, the present study was undertaken to compare thesecompounds for the ability to attenuate plasma and liver biochemicalchanges associated with a toxic dose of APAP.

Pandya et al., (J Biomed Sci. 2010 Aug. 24; 17 Suppl 1:S16), reportPoly(ADP-ribose; PARP) is a NAD requiring, DNA-repairing, enzyme playinga central role in pancreatic beta-cell death and in the development ofendothelial dysfunction in humans and experimental animals. PARPactivation is also relevant to the development of complications ofdiabetes. Hence, agents capable of inhibiting PARP may be useful inpreventing the development of diabetes and in slowing down complicationsof diabetes. A comparative study of the binding characteristics to andinhibitory potencies towards PARP and in vivo antidiabetogenic potenciesof taurine (TAU), 3-aminobenzamide (3-AB) and nicotinamide (NIC) showedthe inhibitory potency order being 3-AB>NIC=TAU.

Sakuma et al., (J Control Release. 2010 Dec. 1; 148 (2):187-96),disclose that oligoarginines, which are known as cell-penetratingpeptides, enhance the cellular uptake of poorly membrane-permeablebioactive molecules that are chemically conjugated to them. A novelpolymer, oligoarginine-linked poly(N-vinylacetamide-co-acrylic acid),was prepared with the expectation that the polymers will enhance thecellular uptake of the bioactive molecules that are physically mixedwith them. Oligoarginines were grafted onto the polymer backbone throughthe chemical reaction with acrylic acid functional groups.

Penetratin-1 (Derosssi et al., 1996, J. Biol. Chem. 271, 18188-18193) isa 16-amino acid peptide corresponding to the third helix of thehomeodomain of Antennapedia protein. This peptide is able to translocateacross biological membranes by an energy-independent mechanism and hasbeen used successfully to internalize covalently attached peptides andoligonucleotides and to convey them to the cytoplasm and nucleus of manycell types. Szucova et al., (Phytochemistry. 2011 Feb. 25), disclosecertain N9-substituted derivatives of kinetin as effectiveanti-senescence agents.

Park et al., (J Gen Virol. 2011 Feb. 16) disclose hepatitis B virus Xprotein overcomes cellular senescence provoked by all-trans retinoicacid in HepG2 cells.

Skulachev et al., (Biochimica et Biophysica Acta—Bioenergetics, Volume1787, Issue 5, May 2009, Pages 437-461; Biochemistry (Moscow), 2008,Vol. 73, No. 12, pp. 1329-1342. Published in Russian in) Biokhimiya,2008, Vol. 73, No. 12, pp. 1655-1670) have attempted to preventsenescence via a mitochondrial approach. Antioxidants specificallyaddressed to mitochondria have been studied to determine if they candecelerate senescence of organisms. For this purpose, a project has beenestablished with participation of several research groups from Russiaand some other countries. A new type of compounds comprisingplastoquinone (an antioxidant moiety), a penetrating cation, and adecane or pentane linker has been synthesized. These look promising fortreatment of senescence and age-related diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Melanin Biosynthesis via Shikimate Pathway.

FIG. 2. Enzyme Inhibition Test.

DETAILED DESCRIPTION

Preventing skin aging by targeting multiple causes by a single bullet isof primal scientific and consumer interest. Treatments based on cellularanti-senescence now offer this single solution to multiple skin ailmentsincluding skin aging!

Senescence is the change in the biology of an organism as it ages afterits maturity, which range from those affecting its cells and theirfunction to that of the whole organism. Senescence is not universal, andsenescence is not observed in single-celled organisms that reproducethrough the process of cellular mitosis. Cellular senescence in humanscauses the cells to stop replicating themselves through the process ofmitosis, thus resulting in cellular degradation over a period of time.

Water is a key element for life. However, some organisms have evolved anamazing adaptation (osmoprotection) that allows them to survive undercomplete dehydration conditions for months or years, until water ispresent again, at which time they resume their metabolism and growth.Anhydrobiosis (“life without water”) is found throughout all biologicaldomains, for example in several species of eubacteria, archea, somefungi, certain invertebrate species and “resurrection plants”. Cellularanti-senescence agents act through compatible solutes to preventcellular damage. Osmoprotection has recently been recognized as a newtherapeutic methodology (Messmer, Ophthalmologe. 2007 November; 104(11):987-90). Cellular anti-senescence agents act through compatible solutesto prevent—at least in theory—a hyperosmolar condition from damaging thecellular function.

Cells must maintain an optimal balance of water to stay plump andhealthy. Imagine a face drawn on a balloon and filled with water. Theface will look plump and youthful as the water keeps pressure on theballoon's inside surface. But if the water were to slowly leak (osmosis)out of the balloon, the drawn face would increasingly look wrinkled,tired, saggy, and aged.

There are several reports suggesting that hyperosmolarity inducesinflammation. Schwartz et al., (J Inflamm (Lond). 2009 Jun. 23; 6:21)have shown that there is a the link between hyperosmolarity andinflammation by assessing osmolarity values in vivo during inflammationand compared the inflammatory potential of different osmotic agents andstudied the long-term consequences of hyperosmolarity on cell fate. Theexposure of cells to the different compounds, whatever their molecularweight, has no effect on the secretion of cytokines as long as theosmolarity is below a threshold of 300 mOsm. Higher osmolarities resultin the secretion of proinflammatory cytokines (Interleukin-8,Interleukin-6, Interleukin-1 beta and Tumor Necrosis factor-alpha).

Abolhassani et al. (Inflamm Res. 2008 September; 57(9):419-29) reportthat hyperosmolarity can induce pro-inflammatory cytokine responses.Inflammation appears to be the simple consequence of a shift ofmethylation of Protein Phosphatase 2A, which in turn activates Nuclearfactor-kappa B (NF-kappaB). The production of inflammatory cytokinescauses the acceleration of aging process.

Sarkar et al. (Cancer Lett. 2006 May 8; 236(1): 13-23. Epub 2005 Jun.22) report that a direct relationship exists between aging andincreasing incidences of chronic diseases. In fact, with mostage-associated diseases individuals manifest an underlying chronicinflammatory state as evidenced by local infiltration of inflammatorycells, such as macrophages, and higher circulatory levels ofpro-inflammatory cytokines, complement components and adhesionmolecules. Consequently, treatment with anti-inflammatory agents providesymptomatic relief to several aging-associated diseases, even as remoteas Alzheimer's or Parkinson's disease, indicating that chronicinflammation may play a substantial role in the pathogenesis of thesedisease states. The molecular mechanisms underlying this chronicinflammatory condition during cellular senescence is presently unclear.Cellular damage by oxygen free radicals is a primary driving force foraging and increased activation of redox-regulated transcription factors,such as NF-kappaB that regulate the expression of pro-inflammatorymolecules, has been documented in aged animals/individuals versus theiryoung counterparts. Human polynucleotide phosphorylase (hPNPase(old-35)), a RNA degradation enzyme shown to be upregulated duringdifferentiation and cellular senescence, may represent a molecular linkbetween aging and its associated inflammation. HPNPase (old-35) promotesreactive oxygen species (ROS) production, activates the NF-kappaBpathway and initiates the production of pro-inflammatory cytokines, suchas IL-6 and IL-8. In these contexts, inhibition of hPNPase (old-35) mayrepresent a novel molecular target for intervening in aging-associatedchronic diseases.

Chambers et al. (J Clin Invest. 1987 March; 79(3): 731-7) disclose thathuman urine is cellular anti-senescence for enteric bacteria, permittingE. coli to grow with high concentrations of NaCl and other salts andeven higher concentrations of sucrose and mannitol but not urea. Twomajor cellular anti-senescence compounds in urine have been identified:glycine betaine, and proline betaine. The presence of glycine andproline betaines in human urine may reflect a cellular anti-senescencerole for the kidney.

Chambers et al. (J. Bacteriol. 1987 October; 169(10): 4845-7) furtherreport that glycine betaine is believed to be the most active naturallyoccurring osmoprotectant molecule for Escherichia coli and otherbacteria. It is a dipolar ion possessing a quaternary ammonimum groupand a carboxylic acid group. To examine the molecular requirements forcellular anti-senescence activity, dimethylthetin was compared withglycine betaine. Dimethylthetin is identical to glycine betaine exceptfor substitution of dimethyl sulfonium for the quaternary nitrogengroup. Dimethylthetin was found to be about equally as effective asglycine betaine in permitting E. coli to grow in hypertonic NaCl, andboth compounds were recovered almost completely from bacterial cellsgrown in the presence of hypertonic NaCl. 3-Dimethylsulfonioproprionate,an analog of dimethylthetin observed in marine algae, and3-Dimethylsulfonio-2-methylproprionate was found to be less active.Dimethylthetin may prove useful as a molecular probe to study betainemetabolism and as a model for the development of antibacterial agents.

In modern medicine dry eye syndrome is one of the most common disordersencountered in daily ophthalmological practice. Hyperosmolarity of thetear film is one of the key pathogenetic factors in the development of acommonly subclinical inflammation of the ocular surface, the lacrimalgland and the tear film in dry eye syndrome. Cellular anti-senescenceagents prevent a hyperosmolar tear film from damaging the ocularsurface.

The agents that are known to provide osmoprotection in non-mammalianorganisms and plants include trehalose, maltose, sucrose, palatinose,cellobiose, gentiobiose, turanose, sorbitol, calcium chloride, certainamino acids (such as proline and alpha-glutamate),alpha-D-mannopyranosyl-(1-->2)-alpha-D-glucopyranosyl-(1-->2)-glycerate,Di-myo-inositol 1,1′-phosphate, N(gamma)-acetyl-2,4-diaminobutyrate(NADA), ectoine, glycine betaine, carnitine, pipecolic acid,dimethylsulfoniopropionate, dimethylsulfonioacetate, peptones, taurine,and taltrimide.

While use of humectants and emollients has been a common practice, theapplication of osmoprotection in skin and hair care of mammals has sofar been practically unknown.

Rosas-Rodriguez et al (Life Sci. 2010 Oct. 23; 87(17-18): 515-20; Epub2010 Aug. 18) report enzymes involved in osmolyte synthesis, especiallyoxidative stress affecting osmoregulation in renal cells. Kidney medullacells are exposed to a wide range of changes in the ionic and osmoticcomposition of their environment as a consequence of the urineconcentrating mechanism. During antidiuresis NaCl and ureaconcentrations increase and an efficient urinary concentrating mechanismis accompanied by medullar hypoxia. Medullar hypotonicity increasesreactive oxygen species, a byproduct of mitochondria during ATPproduction. High intracellular ionic strength, hypoxia and elevated ROSconcentration would have deleterious effects on medulla cell function.Medulla cells respond to hypertonicity by accumulating organicosmolytes, such as glycine betaine, glycerophosphorylcholine, sorbitol,inositol, and taurine, the main functions of which are osmoregulationand osmoprotection.

Sagot et al. (Proc Natl Acad Sci USA. 2010 Jul. 13; 107(28): 12652-7;Epub 2010 Jun. 22) report the dipeptide N-acetylglutaminylglutamineamide that was discovered in the bacterium Sinorhizobium meliloti grownat high osmolarity, and subsequently shown to be synthesized andaccumulated by a few osmotically challenged bacteria.

Gouffi et al. (Int J Food Microbiol. 2000 Apr. 10; 55(1-3): 171-4; J.Bacteriol. 1998 October; 180(19): 5044-51) report sucrose, trehalose,maltose, cellobiose, gentiobiose, turanose and palatinose are veryunusual osmoprotectants for Sinorhizobium meliloti, because thesecompounds, unlike other bacterial osmoprotectants, do not accumulate ascytosolic osmolytes in salt-stressed S. meliloti cells. Rather, thesecompounds were catabolized during early exponential growth, andcontributed to enhance the cytosolic levels of the two endogenouslysynthesized osmolytes: glutamate and the dipeptideN-acetylglutaminylglutamine amide.

Talibart et al. (Appl Environ Microbiol. 1997 December; 63(12):4657-63)report the fate of exogenously supplied glycine betaine and the dynamicsof endogenous osmolytes that were investigated throughout the growthcycle of salt-stressed cultures of strains of Sinorhizobium meliloti,which differ in their ability to use glycine betaine as a growthsubstrate, but not as an osmoprotectant. Glycine betaine is onlytransiently accumulated as a cytoplasmic osmolyte, which virtuallyprevents the accumulation of endogenous osmolytes during the lag andearly exponential phases of growth. Then, betaine levels in stressedcells decrease abruptly during the second half of the exponential phase.At this stage, the levels of glutamate and the dipeptideN-acetylglutaminylglutamine amide increase sharply so that the twoendogenous solutes supplant glycine betaine in the ageing culture, inwhich it becomes a minor osmolyte because it is progressivelycatabolized. Ultimately, glycine betaine disappears when stressed cellsreach the stationary phase.

Dominguez-Ferrera et al. (J. Bacteriol. 2009 December; 191(24): 7490-9;Epub 2009 Oct. 16) report the disaccharide trehalose is a well-knownosmoprotectant, and trehalose accumulation through de novo biosynthesisis a common response of bacteria to abiotic stress.

Perez-Arellano et al. (Extremophiles. 2010 July; 14(4): 409-15. Epub2010 Jun. 11) report glutamate kinase, an enzyme involved inosmoprotection in plants and microorganisms, catalyses the first andcontrolling step of proline biosynthesis.

Lynch et al. (Biomaterials. 2010 August; 31(23): 6096-103. Epub 2010 May14) report a biopolymer that has been shown to facilitate efficientdelivery of trehalose, a bioprotectant normally impermeable to thephospholipid bilayer, into ovine erythrocytes. Cellular uptake oftrehalose was found to be dependent on polymer pendant amino acid typeand degree of grafting, polymer concentration, pH, external trehaloseconcentration, incubation temperature and time.

Flanagan et al. (Nutr Metab (Lond). 2010 Apr. 16; 7:30) report topicalapplication of carnitine in dry eye offers osmoprotection and modulatesimmune and inflammatory responses.

Kitko et al. (PLoS One. 2010 Apr. 8; 5(4): 10078) report diverseosmolytes including NaCl, KCl, proline, or sucrose contribute tocytoplasmic pH homeostasis in E. coli, and increase the recovery fromrapid acid shift. Osmolytes other than K⁺ restore partial pH homeostasisin a strain deleted for K⁺ transport.

Iturriaga et al (Int J Mol. Sci. 2009 Sep. 1; 10(9): 3793-810) reporttrehalose, a non-reducing disaccharide, that is widely distributed inNature and has been isolated from certain species of bacteria, fungi,invertebrates and plants that are capable of surviving in a dehydratedstate for months or years and subsequently being revived after a fewhours of being in contact with water. This disaccharide has manybiotechnological applications, as its physicochemical properties allowit to be used to preserve foods, enzymes, vaccines, cells etc., in adehydrated state at room temperature.

Jorge et al (FEBS J. 2007 June; 274(12): 3120-7. Epub 2007 May 22)report the discovery of a new solute, whose structure was established asalpha-D-mannopyranosyl-(1-->2)-alpha-D-glucopyranosyl-(1-->2)-glycerate(MGG). The level of MGG increased notably with the salinity of thegrowth medium up to the optimum NaCl concentration. At higher NaClconcentrations, however, the level of MGG decreased, whereas the levelsof proline and alpha-glutamate increased about five-fold and 10-fold,respectively. MGG plays a role during low-level osmotic adaptation ofPetrotoga miotherma, whereas alpha-glutamate and, to a lesser extent,proline are used for osmoprotection under salt stress. Fernandez et al(J. Bacteriol. 2010 March; 192(6): 1624-33. Epub 2010 January 8) reportthat mannosylglucosylglycerate (MGG), recently identified in Petrotogamiotherma, also accumulates in Petrotoga mobilis in response tohyperosmotic conditions and supraoptimal growth temperatures.

Jung et al (J Membr Biol. 2006; 213(2): 119-33. Epub 2007 Apr. 6) reportamino acid transport is a ubiquitous phenomenon and serves a variety offunctions in prokaryotes, including supply of carbon and nitrogen forcatabolic and anabolic processes, pH homeostasis, osmoprotection,virulence, detoxification, signal transduction and generation ofelectrochemical ion gradients.

Garcia-Estepa et al. (Syst Appl Microbiol. 2006 December; 29(8): 626-33.Epub 2006 Feb. 15) report N(gamma)-acetyl-2,4-diaminobutyrate (NADA),the precursor of the compatible solute ectoine, to function as anosmoprotectant for the non-halophilic bacterium Salmonella entericaserovar Typhimurium.

Pintsch et al. (BMC Biochemistry 2002, 3:10) have shown that cellssteadily face changes of the external osmolarity, to which they have toadapt. To withstand a steep increase in osmolarity, eukaryotic cellsactivate responses like “regulatory volume increase”, accumulation ofcompatible osmolytes and stimulated expression of stress proteins.Recently, an exception from this scheme has been identified:Dictyostelium cells protect themselves against hyperosmolarity bylargely rearranging cellular proteins, whereas no “regulatory volumeincrease”, no accumulation of compatible osmolytes and no change of theexpression pattern of the most abundant proteins were observed. Amongthe translocated proteins identified, cytoskeletal proteins appear to bepredominant. In particular, the rearrangement of actin and myosin II tothe cell cortex beneath the plasma membrane was shown to constitute apivotal element of osmoprotection in Dictyostelium. In this process thedistribution of the actin-associated protein Hisactophilin (a histidinerich; 31 histidine out of 118 amino acids) actin binding protein fromDictyostelium discoideum was investigated in order to gain a betterinsight into osmo-protective mechanism of the cell. Hisactophilin wasfound to be enriched in the cytoskeletal fraction of wild type cellsexposed to hyperosmotic stress. Hisactophilin is both translocated tothe cytoskeleton and phosphorylated during hyperosmotic stress inDicytostelium.

Gupta (U.S. Pat. No. 7,427,690) discloses certain derivatives of aminoacids and peptides with alkylarylketones having formula (I);

Gupta et al., (U.S. patent application Ser. No. 13/015,805) alsodisclose certain derivatives of amino acids, peptides, and amino sugarswith another ketone, aloesin and isomers and salts thereof. For example,the reaction of aloesin with a dipeptide amide, glutamylglutamine amide,forms isomeric compounds of formula (II);

The present invention is a continuation of the above discoveries, whichnow discloses composition comprising a compound of formula (III) that,surprisingly and unexpectedly, treat conditions of mammalian skindegradation resulting from cellular senescence:

-   -   wherein,    -   R¹, R², and R³ are selected from —OH, —NR⁴R⁵, amino sugar, and        —OR⁶; and    -   X is selected from —NH-peptide, —NH—C¹-C²⁰ alkanoyl, —NH-aroyl,        —NR⁴R⁵, and —N═CR⁷R⁸; and    -   R⁴ and R⁵ are selected from H, alkyl, substituted alkyl, aryl,        substituted aryl, heterocyclic, substituted heterocyclic,        amino-alkanoyl, polyhydroxyalkyl, cycloalkyl, and amino sugar;        and    -   R⁶ is selected from H, and C¹-C²⁰ alkyl; and    -   R⁷ and R⁸ are selected from H, alkyl, substituted alkyl, aryl,        substituted aryl, heterocyclic, and substituted heterocyclic;        and    -   wherein said condition for skin degradation is from cancer,        diabetes, radiation treatments, chemotherapy, and sun-burn;        mitochondrial dysfunction, age spots, acne, loss of cellular        antioxidants, collagen loss, loss of skin pliability, loss of        skin suppleness, skin wrinkles including fine lines, oxidation,        damage from radiation, damage from free radicals, damage from        UV, dry skin, xerosis, ichthyosis, dandruff, brownish spots,        keratoses, melasma, lentigines, liver spots, pigmented spots,        dark circles under the eyes, skin pigmentation including        darkened skin, blemishes, oily skin, warts, eczema, pruritic        skin, psoriasis, inflammatory dermatoses, topical inflammation,        disturbed keratinization, skin changes associated with aging,        scalp dryness, skin depigmentation, intracellular dehydration,        and combinations thereof.

The present invention also relates to compounds that are selectiveregulators of Ubiquitin-proteasome pathway, to cosmetic andpharmaceutical compositions containing them, and to their use in theprevention and/or treatment of ailments associated with the dysfunctionof ubiquitin-proteasome pathway, including inflammation, wound healing,skin aging, body enzyme dysfunction, neurodegenerative disorders, andcellular apoptosis.

The examples of formula (III) include formula (IV);

The present invention discloses a composition comprising a salt of thecompound of formula (III), wherein said salt is a metal salt; said metalis selected from the group consisting of Li, Na, K, Ca, Mg, Ti, V, Cr,Mn, Fe, Co, Ni, Cu, Zn and Se.

The present invention discloses a composition comprising a salt of thecompound of formula (III), wherein said salt is an acid salt; said acidis selected from the group consisting of inorganic and organic acids.

The present invention discloses a composition comprising a compound offormula (III) for pharmaceutical, nutraceutical, cosmetic, topical, ororal application.

The present invention discloses a composition comprising a compound offormula (III) to treat a condition of skin degradation selected from thegroup comprising challenged skin from cancer, diabetes, radiationtreatments, chemotherapy, and sun-burn; mitochondrial dysfunction, agespots, acne, loss of cellular antioxidants, collagen loss, loss of skinpliability, loss of skin suppleness, skin wrinkles including fine lines,oxidation, damage from radiation, damage from free radicals, damage fromUV, dry skin, xerosis, ichthyosis, dandruff, brownish spots, keratoses,melasma, lentigines, liver spots, pigmented spots, dark circles underthe eyes, skin pigmentation including darkened skin, blemishes, oilyskin, warts, eczema, pruritic skin, psoriasis, inflammatory dermatoses,topical inflammation, disturbed keratinization, skin changes associatedwith aging, scalp dryness, skin depigmentation, intracellulardehydration, and combinations thereof.

The present invention discloses a method to treat a condition of skindegradation selected from the group comprising challenged skin fromcancer, diabetes, radiation treatments, chemotherapy, and sun-burn;mitochondrial dysfunction, age spots, acne, loss of cellularantioxidants, collagen loss, loss of skin pliability, loss of skinsuppleness, skin wrinkles including fine lines, oxidation, damage fromradiation, damage from free radicals, damage from UV, dry skin, xerosis,ichthyosis, dandruff, brownish spots, keratoses, melasma, lentigines,liver spots, pigmented spots, dark circles under the eyes, skinpigmentation including darkened skin, blemishes, oily skin, warts,eczema, pruritic skin, psoriasis, inflammatory dermatoses, topicalinflammation, disturbed keratinization, skin changes associated withaging, scalp dryness, skin depigmentation, intracellular dehydration,and combinations thereof comprising administering an effective amount ofa composition comprising a compound of formula (III).

For example, the derivatization of cellular anti-senescence compound,glutaminyl-glutamine amide with an amino sugar moiety provides cellularanti-senescence compounds of formula (X) and (XI), both of which havingimproved bioavailability;

The amino sugars suitable for similar derivatization withglutaminyl-glutamine amide and its variously substituted derivativesinclude, among others, glucosamine, galactosamine (chondrosamine),ribamine, allosamine, altrosamine, gulosamine, idosamine, talosamine,ribosamine, arabinosamine, xylosamine, lyxosamine, fructosamine,neuraminic acid (sialic acid), mannosamine, and their optical isomers.

The reaction of a β-amino acid, such as anthranilic acid, with asubstituted glutaminyl-glutamine amide, for example, provides compoundsof formula (XII) and (XIII);

The present invention discloses a composition comprising a compound offormula (XIV);

The present invention discloses a composition comprising a compound offormula (XV);

wherein,R is selected from H, OH, alkyl, substituted alkyl, halogen, oxyalkyl,and oxyaryl; and R¹ is selected from alkyl, substituted alkyl, aryl,substituted aryl, and heterocyclic.

The present invention discloses a composition comprising a compound offormula (XVI);

It is both surprising and unexpected that compounds of the presentinvention treat a condition of skin degradation selected from the groupcomprising challenged skin from cancer, diabetes, radiation treatments,chemotherapy, and sun-burn; mitochondrial dysfunction, age spots, acne,loss of cellular antioxidants, collagen loss, loss of skin pliability,loss of skin suppleness, skin wrinkles including fine lines, oxidation,damage from radiation, damage from free radicals, damage from UV, dryskin, xerosis, ichthyosis, dandruff, brownish spots, keratoses, melasma,lentigines, liver spots, pigmented spots, dark circles under the eyes,skin pigmentation including darkened skin, blemishes, oily skin, warts,eczema, pruritic skin, psoriasis, inflammatory dermatoses, topicalinflammation, disturbed keratinization, skin changes associated withaging, scalp dryness, skin depigmentation, intracellular dehydration,and combinations thereof. Although the exact mechanism of such treatmentbenefits is not known, it is believed to be a result of prevention ofcellular senescence and moderation of ubiquitin-proteasome malfunction.

Ubiquitin-Proteasomes for Cellular Anti-Senescence.

The body constantly produces proteins and degrades proteins that are nolonger needed or are defective. The production and destruction ofproteins, called protein turnover, is a constant, ongoing process thatis crucial for tissue renewal. A well-nourished person synthesizesnearly one pound of protein per day. Proteins that are broken downbalance this protein gain. The process of protein breakdown, calledproteolysis, is essential to cell survival. Numerous proteolytic systemsexist in mammalian cells, the most important of which are the lysosomes,the ubiquitin-proteasome pathway, and enzymes called calpains. Lysosomesare small cell components that contain specific enzymes (proteases),which break down proteins. In the ubiquitin-proteasome pathway, proteinsthat are to be degraded are first marked by the addition of ubiquitinmolecules and then broken down by large protein complexes calledproteasomes. Calpains are proteases that are involved in severalphysiological processes, including the breakdown of proteins that givecells their shape and stability. The ubiquitin-proteasome system is nowconsidered the major system involved in intracellular proteindegradation. Two major components of this system are (1) three enzymesthat add a small protein called ubiquitin onto substrate proteinsdestined for degradation, and (2) the proteasome, a rather largecellular particle composed of several smaller protein subunits, whichexecutes the actual proteolysis. By degrading short-lived regulatoryproteins, the ubiquitin-proteasome system controls basic cellularprocesses such as cell division, cell signaling, and gene regulation.The system also removes misfolded, damaged proteins, and in certainimmune cells it breaks down foreign proteins into pieces calledantigenic peptides, which can then be transported to the cell surface toinduce an immune response [Ulrich, Current Topics in Microbiology andImmunology, vol 268, 137-174 (2002)].

Ubiquitin is a small protein that occurs in most eukaryotic cells. Itsmain function is to mark other intracellular proteins for destruction,known as proteolysis. Several ubiquitin molecules attach to thecondemned protein (polyubiquitination), and polyubiquitinylated proteinthen moves to a proteasome, a barrel-shaped structure where theproteolysis occurs. Ubiquitin can also mark transmembrane proteins (forexample, receptors) for removal from the membrane.

Ubiquitin consists of 76 amino acids with two sequentially linkedglycine moieties at the carboxyl terminal and has a molecular mass ofabout 8500 amu. It is highly conserved among eukaryotic species: Humanand yeast ubiquitin share 96% amino acid sequence identity.

The process of marking a protein with ubiquitin consists of a series ofsteps; (1) Activation of ubiquitin—the carboxyl group of the terminalglycine of ubiquitin binds to the sulfhydryl group —SH of anubiquitin-activating enzyme E1. The sulfhydryl group is a cysteineresidue on the E1 protein. This step requires an ATP molecule as anenergy source and results in the formation of a thioester bond betweenubiquitin and E1; (2) Transfer of ubiquitin from E1 to theubiquitin-conjugating enzyme E2 via trans (thio) esterification; (3)Then, the final transfer of ubiquitin to the target protein can occureither directly from E2 (this is primarily used when ubiquitin istransferred to another ubiquitin already in place, creating a branchedubiquitin chain) or via an E3 enzyme, which binds specifically to bothE2 and the target protein. The target protein is usually a damaged ornon-functional protein that is recognized by a destruction-targetingsequence. Ubiquitins then bind to a lysine residue in the target proteinvia the transformation of thioester bond into an iso-peptide bond,eventually forming a tail of at least four ubiquitin molecules. Theresulting ubiquitin-linked protein, called ubiquitin-protein conjugate,then can be recognized and degraded by the proteasome into peptides.This is the typical way to mark specific proteins for proteolysis. Afunctional proteasome (also called 26S proteasome) is composed of asmaller barrel-shaped core and two “caps” that are attached to the eachend of the core. The proteasome core consists of four stacked ringscontaining two types of subunits, all facing into a central cavity.These subunits together have at least five distinct proteinaseactivities that cleave proteins at different sites. The “caps” at eachend of proteasome perform a regulatory function. Each cap is composed ofmultiple subunits with numerous functions. These subunits recognize theubiquitinylated protein, cut off the ubiquitin chains from this protein,thereby “unfolding” the protein, and open the channel inside theproteasome core so that the protein can enter the channel fordegradation; and (4) Finally, the marked protein is digested in the26S-proteasome into small peptides, amino acids (usually 6-7 amino acidsubunits). Although the ubiquitins also enter the proteasome, they arenot degraded (despite their protein structure) and may be used again.

Proteasomes are large multi-subunit protease complexes, localized in thenucleus and cytosol, which selectively degrade intracellular proteins.Proteasomes play a major role in the degradation of many proteins thatare involved in cell cycling, proliferation, and apoptosis.Ubiquitin-proteasome pathway is well known in the prior art.

Intracellular proteolysis is the most recently discovered regulatorysystem of cellular physiology. Everything from cell division,development, and differentiation to cellular senescence has aproteolytic component. There is no simpler way to stop a physiologicalprocess than to destroy one of the components of a pathway in acontrolled fashion. The discovery of the role of ubiquitin in theproteolytic pathway earned Aaron Ciechanover, Avram Hershko and IrwinRose the 2004 Nobel Prize in Chemistry. Several books have becomeavailable that further reveal the importance of ubiquitins in humanbiology and human disease control, some of which are included herein forreference only: Ubiquitin and the Chemistry of Life, Mayer et al., JohnWiley, 2005; Ubiquitin, Rechsteiner et al, Plenum Press, 1988; TheUbiquitin System, Schlesinger et al., Cold Spring Harbour Lab, 1988;Ubiquitins and the Biology of the Cell, Peters et al., Plenum Press,2001; Self-Perpetuating Structural States in Biology, Disease, andGenetics (2002), Proceedings of the National Academy of Sciences.

A wide variety of neurodegenerative disorders are associated with theaccumulation of ubiquitinylated proteins (if they are not furtherdegraded by Proteasomes) in neuronal inclusions, and also with signs ofinflammation. In these disorders, the ubiquitinylated proteinaggregates, which will be seen as a foreign body by immune system, maythemselves trigger the expression of inflammatory mediators, such ascyclooxygenase 2 (COX-2). Impairment of ubiquitin-proteasome pathway maycontribute to this neurodegenerative and inflammatory processes.Products of COX-2, such as prostaglandin J2, can, in turn, increase thelevels of ubiquitinylated proteins and also cause COX-2 up-regulation,creating a self-destructive feedback mechanism [Zongmin Li et al.,International Journal of Biochemistry and Cell Biology, vol. 35, 547-552(2003)].

The disruption of the Ubiquitin-proteasome pathway can result fromdamaging events, such as aging-induced decrease in proteasome function[Carrard et al., International Journal of Biochemistry and Cell Biology,vol. 34, 1461 (2002)], oxidative stress [Shringarpure et al., FreeRadical Biology Medicine, vol. 32, 1084-1089 (2002)], and production ofneurotoxic molecules from mutations. A dysfunctionalubiquitin-proteasome pathway may then cause proteins that are normallyturned over by this pathway to aggregate and form inclusions. One of themechanisms by which the abnormal accumulation of ubiquitinylatedproteins may mediate neurodegradation is by triggering an inflammatoryresponse. Inflammation is a natural defense against diverse insults,intended to remove damaging agents and to inhibit their detrimentaleffects. Treatment of neurons with proteasome inhibitors, oxidativestressors, or cyclopentenone prostaglandin J2 elicits accumulation ofubiquitinylated proteins and cytotoxicity in a concentration-dependentmanner. These agents also increased the neuronal levels of COX-2 andprostaglandin E2. COX-2 is the pro-inflammatory and inducible form ofcyclooxygenases, which are enzymes that catalyze the rate-limiting stepin the biosynthesis of prostaglandins, prostacyclins, or thromboxane A2from their precursor arachidonic acid. Cyclooxygenases are bifunctionalhemoproteins that catalyze the cyclooxygenation of arachidonic acid toPGG2 followed by the hydroperoxidation of PGG2 to PGH2. Specificenzymes, such as reductases, isomerases, and synthases, then convertPGH2 to other PGs (prostaglandins) and thromboxane A2. Reactive oxygenspecies (ROS) produced during this biosynthetic pathway are known tocontribute to tissue damage. The pro-oxidant effect of prostaglandin J2could me mediated by its cyclopentenone ring that contains analpha-beta-unsaturated carbonyl group that can react with sulfhydrylgroup of cysteine residues in glutathione and cellular proteins toinhibit ubiquitin isopeptidase activity. This may also contribute to theaccumulation of ubiquitinylated proteins. This toxic positive feedbackmay create a self-destructive mechanism that contributes to theneurodegenerative process. Neurodegenerative disorders, such asAlzheimer's disease, Parkinson's disease, and amylotropic lateralsclerosis, found to be associated with the accumulation ofubiquitinylated proteins in neuronal inclusions also exhibit signs ofinflammation. Ross et al. [Trends Cell Biol., vol. 14(12):703-11 (2004)]provide a detailed discussion of the ubiquitin-proteasome pathway inParkinson's disease and other neurodegenerative diseases. Burger et al.[Eur. J. Cancer, vol. 40(15):2217-29 (2004)] provide an insight into theubiquitin-mediated protein degradation pathway in cancer therapeuticimplications. A book edited by Peters et al, “Ubiquitin and the Biologyof the Cell”, Plenum Publishing, provides information on the importanceof ubiquitin in modulating cellular functions.

The modulation of ubiquitin-proteasome pathway can be achieved inseveral manners that includes, (1) the inhibition of thioester bondformation between ubiquitin and cysteine moiety of ubiquitin activatingenzyme (E1, E2, or E3), (2) the inhibition of iso-peptide bond formationbetween ubiquitin and lysine moiety of target protein (3) the inhibitionof ubiquitin-proteasome complex, (4) acceleration of proteolysis byubiquitin-proteasome complex (acceleration of proteasome ligase, E3,action), (5) selective inhibition of cyclooxygenase enzyme, (6) use ofthiol reducing antioxidants, (7) caspase inhibitors, and (8) use ofmolecular chaperones to attenuate the accumulation of ubiquitinylatedproteins. The molecular chaperones could thus be highly beneficial inthe reduction of inflammation caused by accumulatingubiquitin-proteasome complex, which could be useful for the treatment ofskin aging, inflammation, ulcer and wound healing, and enzymemalfunction related ailments, and this aspect is the focal point of thepresent invention.

Ubiquitin contains 76 amino acids (one letter code:MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG), of which gly-gly dipeptide is at thecarboxy-terminal. It is believed that the compounds of the presentinvention block the above gly-gly binding site, thus acting as molecularchaperones to attenuate the accumulation of ubiquitinylated proteins.

Acne, Rosacea, and Facial Oil Control Benefits.

Acne is caused by a combination of several factors. In a previousdisclosure (U.S. patent application Ser. No. 10/248,691; filed Feb. 10,2003; now abandoned) the present inventor has discussed that acne is agroup of diseases whose initial pathology is the comedo and includesacne vulgaris, neonatal acne, infantile acne, and pomade acne. There areapproximately 45 million people who suffer from acne in America alone.The disease is so common in youth at their puberty that it often hasbeen termed physiological. Although acne stops appearing for most peopleby the age of 25, some people, the majority of them are women,experience the disease well into their adult life. This “adult acne”differs from teenage acne in location and that it tends to be moreinflammatory with fewer comedones. As the human concern for facialbeauty continues to receive heightened marketing attention, the cure forvarious forms of acne has received much attention, as evidenced by thenumber of patents and patent applications that have appeared recently.The patent literature abounds with acne treatments. From January 2001 toJanuary 2003 time period over 900 patent applications were published inU.S. patent applications computer database search that related to acne.From 1975 to January 2003, there were over 9000 patents issued by theU.S. Patents Office that had some reference to acne. From these data, itwould become obvious that a suitable solution to this problem has eludedpast efforts.

The disease of acne is characterized by a great variety of clinicallesions. Although one type of lesion may be predominant (typically thecomedo), close observation usually reveals the presence of several typesof lesions (comedones, pustules, papules, and/or nodules). The lesionscan be either non-inflammatory or, more typically, inflammatory. Inaddition to lesions, patients may have, as the result of lesions, scarsof varying size. The fully developed, open comedo (i.e., a plug of driedsebum in a skin pore) is not usually the site of inflammatory changes,unless the patient traumatizes it. The developing microcomedo and theclosed comedo are the major sites for the development of inflammatorylesions. Because the skin is always trying to repair itself, sheaths ofcells will grow out from the epidermis (forming appendageal structures)in an attempt to encapsulate the inflammatory reaction. Thisencapsulation is often incomplete and further rupture of the lesiontypically occurs, leading to multi-channeled tracts as can be seen inmany acne scars.

In general, there are four major principles presently governing thetherapy of acne: (i) correction of the altered pattern of follicularkeratinization; (ii) decrease sebaceous gland activity; (iii) decreasethe follicular bacterial population (especially P. acnes) and inhibitthe production of extra cellular inflammatory products through theinhibition of these microorganisms, and (iv) produce ananti-inflammatory effect. Acne is a chronic inflammatory diseaseaffecting the sebaceous glands. Acne lesions primarily involve thesebaceous glands located on the face, neck, chest and back. Both closedcomedones (blackheads) and open comedones (whiteheads) are caused byhyperkeratinization of the infundibulum of the sebaceous duct. Thesekeratinous plugs block the flow of sebum. These dilated ducts aboundwith the colonies of Propionibacterium acnes and other fat splittingorganisms. The clinically evident open and closed comedones and themicroscopic microcomedo are the signal lesions of acne. The acne processresults from a cascade of events. First, at puberty a spike in androgenproduction heralds an increase in sebum production and begins thehyperkeratinization process causing microcomedones and sebum blockade.With this blockage, the number of resident follicular flora increasesdramatically. These bacteria produce inflammatory products, whichpermeate through thin walls of dilated sebum-filled duct. Once in theperifollicular dermis, they trigger the body's own immune defenses (bothacute and granulaomatous) to produce the characteristic inflammatorypapules, pustules and nodules characteristic of inflammatory acne. Theterm “acne” is used herein as a general term to include inflammatorydiseases of the pilosebaceous unit. In the medical field, the specifictype of acne is usually indicated by a modifying term, although the termacne is frequently used alone to designate common acne or acne vulgaris.

Thus, there are four factors that are believed to be the contributors ofacne: (1) Increased sebum production; (2) Comedo formation, in which thefollicular infundibulum hypercornifies, hyperkeratinizes, andhypodesquamates; (3) Colonization of the follicule by anaerobicPropionibacterium, mainly P. acnes; and (4) The host's inflammatoryresponse. The above four factors are interrelated to each other. Sebumis comedogenic and causes inflammation by itself. Propionibacteriumacnes is a relatively slow growing, (typically) obligate anaerobegram-positive bacterium that is linked to the skin condition acne. Ananaerobic organism or anaerobe is any organism that does not requireoxygen for growth. Obligate anaerobes will die when exposed toatmospheric levels of oxygen.

The Propionibacterium has high lipolytic activity and liberates freefatty acids from sebum lipids. The free fatty acids have been shown tocause marked inflammation. The microorganisms also produce otherextracellular enzymes such as proteases and hyaluronidases, andchemotactic factors, which may be important in the inflammatory process.It would thus be advantageous to provide relief from all of the abovefour principal causes of acne.

Rosacea is a common facial dermatitis that currently affects anestimated 13 million Americans. It is a chronic and progressivecutaneous vascular disorder, primarily involving the malar and nasalareas of the face. Rosacea is characterized by flushing, erythema,papules, pustules, telangiectasia, facial edema, ocular lesions, and, inits most advanced and severe form, hyperplasia of tissue and sebaceousglands leading to rhinophyma. Rhinophyma, a florid overgrowth of the tipof the nose with hypervascularity and modularity, is an unusualprogression of rosacea of unknown cause. Ocular lesions are common,including mild conjunctivitis, burning, and grittiness. Blepharitis, themost common ocular manifestation, is a nonulcerative condition of thelid margins. Rosacea most commonly occurs between the ages of 30 to 60,and may be seen in women experiencing hormonal changes associated withmenopause. Women are more frequently affected than men; the most severecases, however, are seen in men. Fair complexioned individuals ofNorthern European descent are most likely to be at risk for rosacea;most appear to be pre-disposed to flushing and blushing.

The cause of rosacea is poorly understood, numerous theories have beenoffered. Hypotheses have included gastrointestinal, psychological,infectious, climatic, and immunological causes, although scientificevidence has not substantiated any of these as primary. Controlledstudies have not demonstrated consistent preponderance ofgastrointestinal symptoms in rosacea patients. Similarly, neither adistinct psychological abnormality nor one pharmacological mechanism hasbeen isolated in rosacea patients. Perhaps the most commonly touted ofthe etiologic theories is based on the presence of Demodex folliculorummites in patients with rosacea; the organism feeds on sebum, and in somecases treatment of demodex infestation has noted improvement in therosacea; however, in a review of 79 biopsies in 1969, Demodexfolliculorum was noted in only 19% of the specimens. A bacterial causefor the disease has been hypothesized, but no consistent findings of onebacterium have been demonstrated. Climate, specifically exposure toextremes of sun and cold, may have an effect on the course of thedisease, but the role of climate in what appears to be a connectivetissue disorder is not clear. An autoimmune process has been suggested,and tissue-fixed immunoglobulins have been reported in patients withchronic inflammation of rosacea, but no other evidence has been found.Other experimental evidence has suggested this disease may represent atype of hypersensitivity reaction. No single hypothesis appears toadequately explain both the vascular changes and the inflammatoryreaction seen in rosacea, leaving the pathogenesis unclear. Morerecently, certain investigators have suggested a connection betweenrosacea and H. pylori, bacteria shown to cause certain gastrointestinalulcers, because symptoms seem to have abated in some ulcer patients alsosuffering rosacea. Nevertheless, the connection between H. pylori androsacea has been questioned. H. Herr, J. Korean Med Sci Oct. 15, 2000;(5):551-4; R. Boni, Schweiz Med Wochenschr Sep. 16, 2000; 130(37):1305-8).

Kang et al. (U.S. Patent Application 20020183399) have recentlyconcluded that rosacea and acne have many common features in their onsetand cure. The topical composition for treating rosacea, which comprisesa combination of an antimicrobial and at least one of (a) ananti-inflammatory and (b) a non-retinoid inhibitor, are very similar fortreating acne, according to Kang, for example. It would thus appearlogical to develop broad-spectrum compositions that can treat both acneand rosacea, although such compositions are still unknown, until now.

Most acne treatments are directed at preventing inflammatory lesions,particularly the larger nodulo-cystic lesions that tend to bedestructive and lead to permanent scarring. In general, visiblecomedones are the only minor cosmetic nuisances and do not lead toinflammatory lesions. Most acne treatment is directed to four areas: (1)Keratinous plugs in sebaceous ducts; (2) Large sebaceous glandsproducing excess sebum; (3) Increased numbers of resident follicularbacteria; and (4) Inflammatory response to chemical mediators passingthrough the follicular wall.

Topical products used to remove comedones are known as comedolytics, themost effective being tretinoin, marketed as a prescription product(Retin A) and by several generic companies. Tretinoin or all-transretinoic acid is the naturally occurring metabolite of Vitamin A.Tretinoin increases epidermal cell turnover, thus causing comedolysisand most importantly prevents the formation of new keratinous plugs.Applications of tretinoin are normally once a day at bedtime. Dryness,stinging and redness sometimes accompany the applications. Importantly,improvement is usually not seen for 6-8 weeks. Adapalene 0.1% (Differin)is a topical retinoid like tretinoin. Available by prescription only,the gel is usually applied once nightly. Side effects include frequentscaling, burning, redness and dryness. Improvement is delayed and is notevident for 4-8 weeks. Sodium sulfacetamide 10%/sulfur 5% (Sulfacet-R)is also available by prescription only. It is a lotion withantibacterial and comedolytic action. As with tretinoin, improvement isseen in 4-8 weeks. Salicylic acid 2% is an over the counter product thatexhibits mild comedolytic activity.

The only products that have anti-sebum activity are estrogens and 13cis-retinoic acid (isotretinoin) and these must be used systemically tobe effective. Isotretinoin (Accutane) is a metabolite of Vitamin Aavailable by prescription only. Isotretinoin is used to treat onlysevere cystic or conglobate acne. Because of its teratogenic properties,birth defects can occur. Isotretinoin is a powerful drug and can elevatetriglycerides, total cholesterol and decrease high-density lipoproteins(HDL). Other side effects include dry skin, dry eyes, itching,headaches, nosebleed, and photosensitivity. It is generally taken for4-months to see improvement. Recently, one brand of oral contraceptivehas been approved for the treatment of acne for patients who requestbirth control.

A number of topical and systemic agents are used to lower the number ofbacteria that colonize the follicular duct. These include benzoylperoxide (BP), BP 5%/erythromycin 3% (Benzamycin). BP has antibacterialactivity and drying effects and is available over the counter or byprescription. Moreover, it has been recently reported that benzoylperoxide seems to induce free radical production that can produce skinchanges that qualitatively resemble ultraviolet B damage, e.g.,increases in epidermal thickness, and deleterious changes in elastin andglycosaminoglycans content (Ibbotson, S. H., et al., J. Inves. Derm.,1999, 112: 933-938). In addition, Benzoyl peroxide is highly reactive,and is thus difficult to stabilize in practical compositions. BP isapplied once or twice daily for 1-2 months. BP can produce erythema andpeeling of skin. BP is often tried first for both non-inflammatory andmild inflammatory acne. Other topical antibiotics include clindamycinand erythromycin. These are used as solutions, lotions or gels byprescription only. Usually they are applied once or twice daily andresults are seen in 1-2 months. Azelaic acid 20% (Azelex) also has mildantibacterial effects. Systemic antibiotics include tetracycline and itsanalogs, which are used in low doses for years or until the end of theacne prone years. Most patients with mild inflammatory acne receive acombination of topical antibiotics and tretinoin or other retinoid.Bacterial resistance does occur so antibiotics may be changed or BP issubstituted since resistance does not occur with BP. More severe acnerequires systemic antibiotics and topical retinoid. The most severe mustreceive oral isotretinoin for 4-5 months.

There are no drugs that directly affect the inflammatory acne. Theretinoids do have some anti-inflammatory properties, but these arepoorly described. Topical steroid and even systemic steroids have beenused to abort a severe flare of fulminant acne, but these are limiteduses because of the side effects. Benzoyl peroxide gels are sometimesused as first aid on acne lesions. These function as a “drawingpoultice”, but data supporting this use is not available.

The treatment for acne centers on opening the pore, killing P. acnes,reducing sebum production and regulating inflammatory responses.Retinoids are the agents to reduce sebum production and open the pore.As a topical agent, Differin (adapalene) or Retin-A (tretinoin) is usedfor mild and moderate acne. Isotretinoin, an oral drug, is veryeffective but reserved for the severe and resistant acne because of itsteratogenicity, hepatotoxicity, elevating triglyceride level and otherside effects.

For topical applications, the Food & Drug Administration (FDA) hasapproved the following ingredients for marketing topical acne productsin the USA (Code of Federal Regulations, 21CFR333.310); (1) Resorcinol(2%, in combination only); (2) Resorcinol monoacetate (3%, incombination only); (3) Salicylic acid 0.5 to 2 percent, and (4) Sulfur 3to 10 percent.

Salicylic acid has been used to treat acne for some time. Salicylic aciddries the skin, which helps in acne management, but it also causes skinirritation in perilesional skin areas of acne patients, especiallypatients with sensitive skin, and in some cases the erythema is extreme.Salicylic acid is also pH-sensitive, as in neutralized forms, such assodium salicylate or triethanolamine salicylate; there is a loss ofefficacy due to poor bioavailability. In free acid form, salicylic acidis absorbed rapidly and transported into bloodstream. This is the reasonfor its irritation-causing problems. It would thus be advantageous ifsalicylic acid can be provided in a form that is slow to absorb intodeeper layers of skin for its maximum topical bioavailability andanti-acne efficacy.

Topical and oral antibiotics, especially tetracycline, erythromycin, andclindamycin, are sometimes prescribed for patients with inflammatorypapules and pustules. However, in addition to the undesirability ofantibiotic overuse in general, which can lead to enhance susceptibilityto infection, disadvantages to such treatments include phototoxicity andinteractions with other medications. Other factors that play a role inexacerbating acne, including oil-based cosmetics and some drugs (e.g.,androgenic hormones, high-progestin birth control pills, systemiccorticosteroids, and iodide- and bromide-containing agents) are oftenminimized during acne treatment. Besides the side effects of theantimicrobial agents, development of resistant microorganisms has becomean important issue nowadays. The number of patients harboring resistantP. acnes has been shown to be growing. For this reason, it would beadvantageous to exclude antibiotics and antibacterial agents fromtopical preparations for acne.

For efficacious topical treatments, it would thus be advantageous toinclude the following six-prong provisions to control fundamentalelements that can provide control of both acne and rosacea in a singlecomposition: (1) Control of excess sebum production; (2) Control ofundesirable bacteria and mites; (3) Control of inflammation; (4)Enhanced desquamation of follicular infundibulum cells; (5) Reduction ofirritation from anti-acne and anti-rosacea compositions themselves; and(6) An enhancement of the topical bioavailability of anti-acne andanti-rosacea compositions.

Since the resistance to bacteria is becoming a problem, it would beadvantageous to control bacteria without using an antibacterial agent.Also, salicylic acid is being one of the most favored and inexpensiveingredients to control acne, albeit its irritation causing side effects,it would be advantageous to devise methodologies to increase bothtopical bioavailability and anti-acne efficacy of salicylic acid with areduction in its irritation causing side effects.

The prior art literature abounds with acne and rosacea treatments. FromJanuary 2001 to January 2003 time period over 900 patent applicationswere listed in U.S. patent applications computer database search thatrelated to acne. From 1975 to January 2003, there were over 9000 patentsissued by the U.S. Patents Office that had some reference to acne. Inthe same period, there were over 400 patents that had a reference torosacea. It may also be appreciated that the study and treatment ofrosacea has been a long-time concern of the medical community. Forexample, about 1,000 medical papers have been published on this subject.From these data, it would become obvious that a suitable solution toacne and rosacea problems has not yet been found. A discussion of thepatents and patent applications most pertinent to the present inventionfollows. U.S. Patent Application 20030021855 (Perricone) discloses acneprevention by the topical application of compositions containing analkanolamine such as dimethylaminoethanol, in combination with tyrosineand a sulfur ingredient such as lipoic acid or glutathione. Suchalkanolamines have strong amine odor that is objectionable to consumersfor application on face. Moreover, several such alkanolamines have ahigh pH that can cause irritation. U.S. Patent Application 20030021816(Kang) discloses an immunosuppressant compound, a second activeingredient selected from the group consisting of comedolytics,antibacterials, anti-inflammatory, retinoids, glucocorticoids, andmixtures thereof, and a dermatologically acceptable carrier for acnetreatment. Such immunosuppresants are not readily available for commonuse. U.S. Patent Application 20020192298 (Burrell) relates to the use ofantimicrobial metals, preferably silver for the treatment of acne. It ispreferred that the use of any antimicrobial agents for acne treatment beminimized or eliminated due to development of resistant bacteria. U.S.Patent Application 20020172672 (Sieberg) is directed to the use ofserine proteases, either alone or in combination with a retinoidcompound in a pharmaceutical or cosmetic composition for acne treatment.Such enzyme preparations can cause serious skin allergy in some humans.U.S. Patent Application 20020155180 (Goodman) discloses treatment ofacne that comprises topically applying an effective amount of a sawpalmetto berry extract and one or more constituents that enhancepenetration of the extract into hair follicle sebaceous glands. Thisdisclosure is specific to one ingredient, hence of limited application.U.S. Patent Application 20020151527 (Wiegand) discloses a method forreducing the number and severity of acne lesions comprisingadministering a sensory regimen to down regulate the activity of thehypothalamus-pituitary-adrenal axis, in combination with theadministration of a topical anti-acne composition comprising ananti-acne agent selected from salicylic acid, sulfur, lactic acid,glycolic acid, pyruvic acid, urea, resorcinol, N-acetylcysteine,retinoic acid, benzoyl peroxide, octopirox, triclosan, azelaic acid,phenoxyethanol, phenoxypropanol, flavinoids, derivatives thereof, andmixtures thereof. The problems of salicylic acid irritation and lowtopical bioavailability and the use of antibacterials are still noteliminated by Wiegand. U.S. Patent Application 20010056071 (Pelicchia)discloses the application of antioxidant resveratrol for acne treatment.U.S. Pat. No. 6,451,773 (Oester et al.) discloses a combination ofchitosan with azelaic acid, benzoyl peroxide, retinoic acid, salicylicacid, or mixtures thereof, for the treatment of acne. Chitosan is usedas a film-forming agent for topical application of other activeingredients for better adhesion to skin surface. While topicalbioavailability is enhanced, the skin irritation and other problems ofsalicylic acid and azelaic acid use are not reduced. U.S. Pat. No.6,440,994 (Sanders) discloses acne treatment using a mixture ofantihistamines and anti-inflammatory agents. This does not provide amultifaceted treatment objective. U.S. Pat. No. 6,436,417 (Singh)discloses solubilized forms of salicylic acid for acne treatment. Suchsolubilized forms absorb more quickly, reaching bloodstream at a fasterrate. Both the topical anti-acne efficacy may be lower and skinirritation may be higher for such compositions. U.S. Pat. No. 6,433,024(Popp et al.) discloses topical anti-acne compositions based on benzoylperoxide, an alpha hydroxy acid, a moisturizer, an isosorbide and adetergent. These compositions contain several skin irritatingingredients. U.S. Pat. No. 6,365,623 (Perricone) discloses one preferredembodiment that contains a combination of lipoic acid, an alpha-hydroxyacid, and dimethylaminoalcohol. Lipoic acid is also claimed to curerosacea (U.S. Pat. No. 6,472,432; Perricone). U.S. Pat. No. 6,262,117(Sefton) discloses acne treatment based on a combination of benzoylperoxide and azelaic acid. The poor stability of benzoyl peroxide andthe skin irritation of either benzoyl peroxide or azelaic acid are stillunsolved in Sefton disclosure. U.S. Pat. No. 6,168,798 (O'Halloran etal.) discloses an alcoholic solution of salicylic acid and salicylatesfor acne treatment. The rapid absorption of such clear solutions intoskin would reduce the topical bioavailability of the active ingredientsin such compositions. U.S. Pat. No. 5,989,523 (Fitzjarrell et al.)discloses a topical spray comprising niacinamide, Aloe Vera extract andNaPCA in a water carrier base. U.S. Pat. No. 5,910,312 (Fried) disclosesan anti-acne composition comprising benzoyl peroxide, salicylic acid,and a vasoconstrictor in an inert carrier. Benzoyl peroxide has beensuggested for treating acne vulgaris. (See U.S. Pat. No. 4,387,107.) Formany years, benzoyl peroxide has been proven to be a particularlypowerful keratolytic and anti-seborrhic agent, as well as being endowedwith antibacterial properties. Topical benzoyl peroxide compositions,including a vehicle to enhance the efficacy thereof, are known (See U.S.Pat. No. 4,411,893). Topical compositions of benzoyl peroxidecombination with antibiotics are also known. (See U.S. Pat. Nos.4,407,794; 4,692,329 and 4,387,107). The problems of skin irritationfrom benzoyl peroxide or salicylic acid, and the chemical instabilityand reactivity of benzoyl peroxide are still not solved; complex,dual-chamber delivery systems (such as U.S. Pat. Nos. 6,462,025 and6,448,233) have been disclosed.

Rosacea is, while rare among colored races, common among races with alight-colored skin, especially among white races, and many cases occuramong them. It is divided according to the symptoms into the firstdegree (telangiectatic rosacea on the forehead, cheeks, dorsum nasi),the second degree (acne rosacea, coexistence of follicular papules andpustules), and the third degree (rhinophyma, dark red tumor and dilatedpore on apex nasi). It starts with facial flush (redness) and eventuallyinvolves serious impairment of appearance, developing papules, pustules,rhinophyma and tumor on apex nasi, it is also accompanied by seborrheaor enhancement of feeling of heat on the face due to emotional stress orchange of environmental temperature. Thus, these symptoms give a patientmental and physical suffering. For the time being, the real cause ofrosacea is unknown (Hifuka Chirya Handbook, pp. 380-381, Nanzando (1987)and Gerd Plewing, Albert M. Kligman, ACNE and ROSACEA, 2nd, CompletelyRevised and Enlarged Edition, pp. 431-454, Springer-Verlag (1993)).Rosacea is apt to be confused with acne. Rosacea, which can coexist withacne, essentially differs from acne. It is characterized by facial flushdue to vascularization and proceeds with acne rosacea and tumor on apexnasi. The etiology of rosacea is not fully known, however, at least fourfactors or co-factors have been suggested. The first of these isendocrine in that the disease occurs most frequently in women betweenthe ages of thirty and fifty. As such, one definite type of rosacea isbelieved to have a hormonal basis. A second factor is vasomotorliability, believed to have some connection with menopause, which bringsabout an impairment of normal or consistent flow of blood to the faceand its capillaries. Therein, excessive flow of blood to the face, i.e.,the well-known “hot flashes” of menopause, is believed to constitute afactor in the disease and its pathogenesis. More particularly, it hasbeen proven that increased skin temperature, as occurs in facialflushing, increases susceptibility to the condition. Rosacea has alsobeen observed as a side effect or immune response to the use of certaincortisone products, which can bring about a severe form of thecondition. Finally, pathology analysis of the expressed contents ofinflamed pustule follicle of the nose in acute rosacea has demonstratedthe existence of demodices, which is a signature of the ectoparasitedemodex folliculorum. Accordingly, in such cases, a specific externalpathogenic factor is evident. This factor is not present in other formsof acne, e.g., acne vulgaris.

However, the information available so far does establish that both acneand rosacea are interrelated, and hence a common treatment for bothwould be highly desirable.

Relative to rosacea treatment compositions, U.S. Pat. Nos. 6,352,724 and5,654,013 (Taylor et al.) discloses rubbing common salt (Sodiumchloride). Sodium chloride is the subject of additional disclosures forthe treatment of both acne and rosacea (U.S. Pat. No. 4,443,442 toSkillern; U.S. Pat. No. 3,867,522 to Kligman). However, such treatmentsonly work by a single biochemical mechanism, that of abrasion anddebridement of the affected skin. Also, once the debridement iscompleted, the affected skin will feel pain, since it will be equivalentto “adding salt to injury”. U.S. Pat. No. 6,174,534 (Richard et al.)provides a composition that contains long chain fatty acids for rosaceatreatment. Although such composition may be suitable for rosacea, suchfatty acids may actually exacerbate acne due to excess sebum-likeactivity from such fatty acids. U.S. Pat. No. 6,136,806 (Hittel)discloses certain synthetic organic molecules for rosacea treatment thatare not commonly available, or available by prescription only in certaincountries. U.S. Pat. Nos. 6,133,310 (Parks) and 5,952,372 (McDaniel)disclose the application of Invermectin in the treatment of rosacea.This ingredient has also been used frequently for the treatment of acne.Invermectin, however, provides relief by a single biochemical mechanism,not a six-prong approach. Moreover, Invermectin is not commonlyavailable. U.S. Pat. No. 5,972,993 (Ptchelintsev) discloses theapplication of certain antioxidants for the treatment of rosacea. Thistreatment is thus based only on a single approach of anti-inflammatoryaction of such antioxidants. U.S. Pat. No. 5,667,790 (Sellers) disclosesthe application of aluminum salts for acne and rosacea treatment. Suchaluminum salts only block the exudation of sebum and provide reliefprobably by astringent action. Their long-term use can actually causeadditional inflammatory response. U.S. Pat. No. 5,885,595 (Corey)discloses esters of retinal for acne and rosacea treatment. U.S. PatentApplication 20020013361 (Perricone) claims the use of lipoic acid. Sincelipoic acid is an antioxidant, it probably works by anti-inflammatorybiochemical mechanism, thus constituting just one-prong treatment. U.S.patent applications 20020172719, 20020054918, and 20020041901 (Murad)disclose pharmaceutical composition and methods for the cleansing ofskin to facilitate the prevention, treatment, and management of skinconditions that include rosacea and acne by a composition that includesa hydroxy acid or tannic acid to exfoliate a portion of the skin,stabilized hydrogen peroxide to facilitate cleansing of the skin, and anantimicrobial agent to inhibit or reduce microorganisms on the skin.Since the overuse of antimicrobial agents can cause further problems, asmentioned earlier, Murad inventions are thus of limited application, oreven to be possibly avoided for any long-term rosacea and acne treatmentregimen.

It is thus both surprising and unexpected that the compositions of thepresent invention relieve the symptoms of acne and also rosacea. Theexact mechanism of this action is not well understood at this time.However, this does not reduce the significance or utility of the presentinvention for consumer applications.

Mazzio et al (U.S. patent application Ser. No. 2004185123) disclose atopical herbal formulation for preventing and/or treating dyshidrosis(pompholyx), non-responsive to topical steroids. The formulation mayalso be used to treat contact dermatitis, eczema, palmoplantarpustulosis and skin infections incurred by invasive pathogens such asmold, fungus and bacteria. The formulation is comprised of plantextracts and niacin, that when combined yield an effective multi-facetedpharmaceutical approach to treating dry skin disorders. The activeingredients within the formula include a combination of dry, aqueous,acid and alcohol extracts of black walnut hull (Ouglans Nigra), wormwood(Artemisia Absinthium), tumeric rhizome (Curcuma Longa), garlic (Alliumsativum), chamomile (Matricaria Chamomile), licorice root (GlycyrrhizaGlabra), St. Johns wort (Hypericum perforatum), aloe vera, niacin andherbal anti-bacterial agents.

The present inventor hypothesizes possible mechanism(s) for anti-acneactivity of the present invention. Acne is caused, among other factors,by Propionibacterium acnes. Most bacteria are greatly dependent on iron(in Fe3+ state) for their metabolic activity. This Fe demand is greaterthat Fe requirements of normal human cells. The bacterial iron transporthas been extensively studies in the prior art, for example Nielands etal. [Adv. Inotg. Biochem., 5, 137 (1983); Struct. Bonding (Berlin), 58,1 (1984)]. The agents responsible for iron transport into and withinbacteria have been extensively studied, and many structural and chemicaldetails have been firmly established. The problem is that iron is notspontaneously available to oxic (aerobic) organisms in an aqueousenvironment because of the very low solubility of ferric hydroxide (pKabout 38). Thus Fe3+ ions at a pH of about 7 have a molar concentrationof only about 10(−18), and simple diffusion into cells could neversuffice to supply their needs. Indeed, simple inward diffusion would notoccur, since iron is already more concentrated than this in the livingcell. Therefore special chelating agents called “siderophores” areproduced by bacteria and ejected into their environment to gather ironand transport it through the cell wall into the cell. In some cases itappears that the chelator at the cell wall releases iron and it passesthrough alone, whereas in others the entire complex enters the cell.

The siderophores are rather diverse chemically but have in common theuse of chelating, oxygen-donor type ligands. A very large number ofsiderophores that have been characterized employ hydroxamate moieties,—CO—N—O(−), as the ligands. The structure of a siderophore, called a“ferrichrome” consists of a cyclic hexapeptide in which three successiveamino acid residues have side chains ending in hydroxamate groups.

Another type of siderophore, especially common in prokaryotes such asenteric bacteria is called an “enterobactin”; the ligating units arecatecholate anions that also chelate very effectively [Raymond et al.,J. Am. Chem. Soc., 107, 6920 (1985)].

Iron-Sulfur proteins are relatively low molecular weight compoundsconsisting of peptide chains bound though cysteine sulfur atoms to redoxcenters that consist either of one iron atom or a cluster of iron andsulfur atoms, the latter often being called “inorganic” sulfur atoms todistinguish them from the sulfur atoms of the cysteine residues. Theterm “rubredoxin” is used for those with one iron atom, while thosecontaining clusters are called “ferredoxins”.

Rubredoxins are found in anoxic (anaerobic) bacteria where they arebelieved to participate in biological redox reactions. They arerelatively low molecular weight proteins (about 6000 amu) containingonly one iron atom. In the best-characterized rubredoxin, from thebacterium Clostridium pasturianum, the iron atom, which is normally inthe III oxidation state, is surrounded by a distorted tetrahedron ofcysteinyl sulfur atoms. The Fe—S distances range from 2.24 to 2.33Angstroms (A), and the S—Fe—S angles from 104 to 114 degrees. When theFe (III) is reduced to Fe (II) there is a slight (0.05 A) increase inthe Fe—S distances. However, Mossbauer spectroscopy shows that Fe isactually present both in (III) and (II) oxidation states. Ferredoxinsare also relatively small proteins (about 6000-12000 amu) in which theredox centers, clusters of two, three, or four iron atoms, each with anequal number of sulfur atoms are held in place by bonds from cysteinesulfur atoms to iron.

From the above discussion it can be seen that a distortion ofrubredoxin, ferredoxin, ferrichrome siderophore, and enterobactinsiderophore can cause a disruption of bacterial metabolism. Thus, thebacteria may not be killed via the antibacterial action, but theirmultiplication by cell division may be hampered for their furthergrowth.

In an unexpected and surprising discovery it has now been found that thecompositions of the present invention bind with rubredoxin moiety ofPrionionibacterium acnes. When this bound form of rubredoxin enters theacne bacterium the cellular redox functions are inhibited. This causesthe acne bacterium to cease its metabolic activity. However, this isonly one mechanism for anti acne activity of the present invention.There are several other possible modes of anti-acne action, as mentionedabove, which are yet unknown for the benefits rendered by the presentinvention. As stated before, this should not preclude the utility ofthis invention.

Control of Dark Spots. Inhibition of Phenylalanine Hydroxylase andPhenylalanine Transaminase.

The biosynthetic pathways from shikimic acid leading to the formation ofmelanin are summarized in FIG. 1 that will be used as a reference forsubsequent discussions.

FIG. 1.

Phenylalanine hydroxylase is responsible for the first step in theconversion of phenylalanine into tyrosine. Tyrosine is required for theproduction of melanin, which gives color to hair and skin. Phenylalaninehydroxylase must work in combination with tetrahydrobiopterin to performthis function. Phenylalanine hydroxylase contains iron in its activesite, and tetrahydrobiopterin is required in proximity to this activesite.

It is both surprising and unexpected that compositions of the presentinvention inhibit phenylalanine hydroxylase. Although the mechanism ofthis inhibition is not fully clear at this time, it is theorized thatthe binding of iron metal at the active site of Phenylalaninehydroxylase (Reaction Step 8, FIG. 6) and/or binding with Fe attetrahydrobiopterin could be the cause for this effect.

Control of Dark Spots. Inhibition of tyrosine transaminase andMonophenol Monooxygenase (Tyrosinase).

Tyrosinase [EC:1.14.18.1] is a complex group of copper monooxygenasesthat catalyses the hydroxylation of monophenols and the oxidation ofortho-diphenols to ortho-quinones. This enzyme, found in prokaryotes andeukaryotes, is involved in the formation of pigments such as melaninsand other polyphenolic compounds. Tyrosinase binds two copper ions (CuAand CuB). It has been shown that three conserved histidine residues bindeach of the two copper ions. The regions around these copper-bindingligands are well conserved and also shared by some hemocyanins, whichare copper-containing oxygen carriers from the hemolymph of manymollusks and arthropods. At least two peoteins related to tyrosinase areknown to exist in mammals, and include TRP-1, which is responsible forthe conversion of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) toindole-5,6-quinone-2-carboxylic acid; and TRP-2, which is themelanogenic enzyme DOPAchrome tautomerase [EC:5.3.3.12] that catalyzesthe conversion of DOPAchrome to DHICA. TRP-2 differs from tyrosinasesand TRP-1 in that it binds two zinc ions instead of copper.

The inhibition of melanin synthesis can thus be achieved via severalpathways, including the inhibition of tyrosine transaminase (inhibitionof amination of hydroxyphenyl Pyruvate or phenyl Pyruvate (Step [7]and/or [4], FIG. 1), which leads to eventual inhibition of tyrosinebiosynthesis. The melanin synthesis can also be blocked by theinhibition of monophenyl monooxygenase (EC 1.14.18.1), which convertstyrosine into dopaquinone via the intermediacy of dopa. In a surprisingand unexpected discovery, the compositions of the present inventioninhibit both tyrosine transaminase and monophenyl monooxygenase. Theprecise mechanism of this inhibition is not known at this time, but itis hypothesized that the compositions of the present invention bind withFe in the active-site of monophenyl monooxygenase. Regardless of theactual biochemical mechanism the importance of this invention remainsunexpected and novel.

Skin Brightening and Antiwrinkle-Antiaging Applications.

The compositions of the present invention provide an unexpectedinhibition of MMP, tyrosinase, and tyrosine biosynthesis enzymes. Thedown-regulation of MMP leads to reduced degradation of connective issuesuch as collagen and fibrin. This results in increased suppleness ofskin, leading to reduced visible skin wrinkles from aging. The decreasedbiosynthesis of tyrosine and dopa, and inhibition of Tyrosinase andtyrosine precursor enzymes leads to skin brightening effects, all ofwhich are both surprising and unexpected when taken as a group of suchdesirable benefits. In normal practice, such group of desirable benefitsis usually achievable only from a combination of several ingredients.The compounds providing good skin brightening are of formula (VII), andisomers and salts thereof.

Wound Healing Applications.

The compositions of the present invention provide an unexpected woundhealing benefit with little scar tissue formation or skin pigmentdiscoloration.

The entire wound healing process is a complex series of events thatbegins at the moment of injury and can continue for months to years.This overview will help in identifying the various stages of woundhealing. [0086]I. Inflammatory Phase. A) Immediate to 2-5 days; B)Hemostasis, (i) Vasoconstriction, (ii) Platelet aggregation, and (iii)Thromboplastin makes clot; C) Inflammation, (i) Vasodilation, (ii)Phagocytosis. [0087] II. Proliferative Phase. A) 2 days to 3 weeks; B)Granulation, (i) Fibroblasts lay bed of collagen, (ii) Fills defect andproduces new capillaries; C) Contraction, [0088](i) Wound edges pulltogether to reduce defect; D) Epithelialization, (i) Crosses moistsurface, (ii) Cell travel about 3 cm from point of origin in alldirections. III. Remodeling Phase. A) 3 weeks to 2 years; B) Newcollagen forms which increases tensile strength to wounds; C) Scartissue is only 80 percent as strong as original tissue.

Wound healing, or wound repair, is the body's natural process ofregenerating dermal and epidermal tissue. When an individual is wounded,a set of events takes place in a predictable fashion to repair thedamage. These events overlap in time and must be artificiallycategorized into separate steps: the inflammatory, proliferative, andmaturation phases. In the inflammatory phase, bacteria and debris arephagocytized and removed and factors are released that cause themigration and division of cells involved in the proliferative phase. Theproliferative phase is characterized by angiogenesis, collagendeposition, granulation tissue formation, epithelialization, and woundcontraction. In angiogenesis, new blood vessels grow from endothelialcells. In fibroplasia and granulation tissue formation, fibroblasts growand form a new, provisional extracellular matrix (ECM) by excretingcollagen and fibronectin. In epithelialization, epithelial cells crawlacross the wound bed to cover it. In contraction, the wound is madesmaller by the action of myofibroblasts, which establish a grip on thewound edges and contract themselves using a mechanism similar to that insmooth muscle cells. As the cells' roles are close to complete, unneededcells undergo apoptosis. In the maturation and remodeling phase,collagen is remodeled and realigned along tension lines and cells thatare no longer needed are removed by apoptosis.

In the inflammatory phase, clotting takes place in order to obtainhemostasis, or stop blood loss, and various factors are released toattract cells that phagocytize debris, bacteria, and damaged tissue andrelease factors that initiate the proliferative phase of wound healing.When tissue is first wounded, blood comes in contact with collagen,triggering blood platelets to begin secreting inflammatory factors.Platelets also express glycoproteins on their cell membranes that allowthem to stick to one another and to aggregate, forming a mass. Fibrinand fibronectin cross-link together and form a plug that traps proteinsand particles and prevents further blood loss. This fibrin-fibronectinplug is also the main structural support for the wound until collagen isdeposited. Migratory cells use this plug as a matrix to crawl across,and platelets adhere to it and secrete factors. The clot is eventuallylysed and replaced with granulation tissue and then later with collagen.Platelets, the cells present in the highest numbers shortly afterwounding, release a number of factors into the blood, including ECMproteins and cytokines, including growth factors. Growth factorsstimulate cells to speed their rate of division. Platelets also releaseother proinflammatory factors like serotonin, brakykinin,prostaglandins, prostacyclin, thromboxane, and histamine, which serve anumber of purposes, including to increase cell proliferation andmigration to the area and to cause blood vessels to become dilated andporous.

Contrary to common belief, the use of any anti-inflammatory agentsduring the early stages of would-healing process is not desirable. Onthe same note, the over-expression of MMP-13 should be controlled fromthe onset of wound healing process to avoid apoptosis of newly formedconnective tissue. Both connective tissue forming agents andanti-inflammatory agents are beneficial during the later stages of woundhealing.

The exact mechanism of topical wound healing by the compositions of thepresent invention is believed to be due to the inhibition of HemeOxidase, the exact nature if which is not yet known. However, thisshould not preclude the practical utility of the present invention intopical wound healing applications.

Treatment of Dandruff.

Recently, identification of Malassezia (formerly known as Pityrosporum,is a genus of related fungi, classified as yeasts; naturally found onthe skin surfaces of many animals including humans) has been aided bythe application of molecular or DNA based techniques. Theseinvestigations show that the Malassezia species causing most skindisease in humans, including the most common cause of dandruff andseborrhoeic dermatitis, is M. globosa (though M. restricta is alsoinvolved). The skin rash of tinea versicolor (pityriasis versicolor) isalso due to infection by this fungus. So far, 10 species of Malasseziahave been identified: M. furfur, M. pachydermatis, M. globosa, M.restricta, M. slooffiae, M. sympodialis, M. nana, M. yamatoensis, M.dermatis, and M. obtuse.

As the fungus requires fat to grow, it is most common in areas with manysebaceous glands: on the scalp, face, and upper part of the body. Whenthe fungus grows too rapidly, the natural renewal of cells is disturbedand dandruff appears with itching (a similar process may also occur withother fungi or bacteria). The number of specimens of M. globosa on ahuman head can be up to ten million.

The compounds of the present invention have shown high activity againstdandruff and seborrhea causing organisms.

The exact amount of each ingredient, or combinations thereof, to be usedfor various applications disclosed in the present invention isdetermined separately for each such application. In general, the amountscan vary from about 0.0001 percent by weight to about 50 percent byweight.

For the treatment of topical wounds, the inclusion of a Matrixmetalloprotease (MMP) inhibitor is additionally beneficial. The said MMPcan be selected, among others, from those disclosed by the presentinventor in U.S. patent application Ser. No. 10/711,775, filed Oct. 4,2004.

The compositions of the present invention can further include additionalpharmaceutical or cosmetic active agent selected from a group ofanti-acne agents comprising of salicylic acid, benzoyl peroxide,resorcinol, resorcinol monoacetate, sulfur, and combinations thereof.

The compositions of the present invention can further include additionalpharmaceutical or cosmetic active agent for topical wound therapy, whichcan be selected, among others, from zinc ascorbate, copper Hyaluronate,zinc Hyaluronate, manganese Hyaluronate, copper Glucosamine complex,zinc Glucosamine complex, manganese Glucosamine complex, copperchondroitin, zinc chondroitin, manganese chondroitin, copperchondrosine, zinc chondrosine, manganese chondrosine, copper oleoresincomplex, zinc aloeresin complex, manganese aloeresin complex, copperaloe emodin, zinc aloe emodin, and manganese aloe emodin.

The compositions of the present invention can be formulated in variouscosmetic and pharmaceutical consumer products utilizing a variety ofdelivery systems and carrier bases. Such consumer product forms includethe group consisting of shampoos, aftershaves, sunscreens, body and handlotions, skin creams, liquid soaps, bar soaps, bath oil bars, shavingcreams, conditioners, permanent waves, hair relaxers, hair bleaches,hair detangling lotion, styling gel, styling glazes, spray foams,styling creams, styling waxes, styling lotions, mousses, spray gels,pomades, shower gels, bubble baths, hair coloring preparations,conditioners, hair lighteners, coloring and non-coloring hair rinses,hair grooming aids, hair tonics, spritzes, styling waxes, band-aids, andbalms.

In another preferred aspect, the delivery system or a carrier base areselected in the form of a lotion, cream, gel, spray, thin liquid, bodysplash, powder, compressed powder, tooth paste, tooth powder, mouthspray, paste dentifrice, clear gel dentifrice, mask, serum, solidcosmetic stick, lip balm, shampoo, liquid soap, bar soap, bath oil,paste, salve, collodion, impregnated patch, impregnated strip, skinsurface implant, impregnated or coated diaper, and similar delivery orpackaging form.

In another preferred aspect, the delivery system can be human body orhair deodorizing solution, deodorizing powder, deodorizing gel,deodorizing spray, deodorizing stick, deodorizing roll-on, deodorizingpaste, deodorizing cream, deodorizing lotion, deodorizing aerosol, andother commonly marketed human body and hair deodorizing compositions,household deodorizing solution, deodorizing powder, deodorizing gel,deodorizing spray, carpet deodorizer, room deodorizer, and othercommonly marketed household deodorizing compositions, animals and petsdeodorizing solution, deodorizing powder, deodorizing gel, deodorizingspray, animals and pets carpet deodorizer, animals and pets roomdeodorizer, and other commonly marketed animal and pet deodorizingcompositions.

In another preferred aspect, the delivery system can be traditionalwater and oil emulsions, suspensions, colloids, microemulsions, clearsolutions, suspensions of nanoparticles, emulsions of nanoparticles, oranhydrous compositions.

Additional cosmetically or pharmaceutically beneficial ingredients canalso be included in the formulated compositions of the presentinvention, which can be selected from, but not limited to skincleansers, cationic, anionic surfactants, non-ionic surfactants,amphoteric surfactants, and zwitterionic surfactants, skin and hairconditioning agents, vitamins, hormones, minerals, plant extracts,anti-inflammatory agents, collagen and elastin synthesis boosters,UVA/UVB sunscreens, concentrates of plant extracts, emollients,moisturizers, skin protectants, humectants, silicones, skin soothingingredients, antimicrobial agents, antifungal agents, treatment of skininfections and lesions, blood microcirculation improvement, skin rednessreduction benefits, additional moisture absorbents, analgesics, skinpenetration enhancers, solubilizers, moisturizers, emollients,anesthetics, colorants, perfumes, preservatives, seeds, broken seed nutshells, silica, clays, beads, luffa particles, polyethylene balls, mica,pH adjusters, processing aids, and combinations thereof.

In another preferred aspect, the cosmetically acceptable compositionfurther comprises one or more excipient selected from the groupconsisting of water, saccharides, surface active agents, humectants,petrolatum, mineral oil, fatty alcohols, fatty ester emollients, waxesand silicone-containing waxes, silicone oil, silicone fluid, siliconesurfactants, volatile hydrocarbon oils, quaternary nitrogen compounds,amine functionalized silicones, conditioning polymers, rheologymodifiers, antioxidants, sunscreen active agents, di-long chain aminesfrom about C.sub.10 to C.sub.22, long chain fatty amines from aboutC.sub.10 to C.sub.22, fatty alcohols, ethoxylated fatty alcohols anddi-tail phospholipids.

Representative saccharides include nonionic or cationic saccharides suchas agarose, amylopectins, amylases, arabinans, arabinogalactans,arabinoxylans, carrageenans, gum arabic, carboxymethyl guar gum,carboxymethyl (hydroxypropyl) guar gum, hydroxyethyl guar gum,carboxymethyl cellulose, cationic guar gum, cellulose ethers includingmethyl cellulose, chondroitin, chitins, chitosan, chitosan pyrrolidonecarboxylate, chitosan glycolate chitosan lactate, cocodimoniumhydroxypropyl oxyethyl cellulose, colominic acid ([poly-Nacetyl-neuraminic acid]), corn starch, curdlan, dermatin sulfate,dextrans, furcellarans, dextrans, cross-linked dextrans, dextrin,emulsion, ethyl hydroxyethyl cellulose, flaxseed saccharide (acidic),galactoglucomannans, galactomannans, glucomannans, glycogens, guar gum,hydroxy ethyl starch, hydroxypropyl methyl cellulose, hydroxy ethylcellulose, hydroxy propyl cellulose, hydroxypropyl starch,hydroxypropylated guar gums, gellan gum, gellan, gum ghatti, gum karaya,gum tragancanth (tragacanthin), heparin, hyaluronic acid, inulin,keratin sulfate, konjac mannan, modified starches, laminarans,laurdimonium hydroxypropyl oxyethyl cellulose, okra gum, oxidizedstarch, pectic acids, pectin, polydextrose, polyquaternium-4,polyquaternium-10, polyquaternium-28, potato starch, protopectins,psyllium seed gum, pullulan, sodium hyaluronate, starchdiethylaminoethyl ether, steardimonium hydroxyethyl cellulose,raffinose, rhamsan, tapioca starch, whelan, levan, scleroglucan, sodiumalginate, stachylose, succinoglycan, wheat starch, xanthan gum, xylans,xyloglucans, and mixtures thereof. Microbial saccharides can be found inKirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, Vol.16, John Wiley and Sons, NY pp. 578-611 (1994), which is incorporatedentirely by reference. Complex carbohydrates found in Kirk-OthmerEncyclopedia of Chemical Technology, Fourth Edition, Vol. 4, John Wileyand Sons, NY pp. 930-948, 1995 which is herein incorporated byreference.

The cosmetically acceptable composition of this invention may includesurface-active agents. Surface-active agents include surfactants, whichtypically provide detersive functionality to a formulation or act simplyas wetting agents. Surface-active agents can generally be categorized asanionic surface-active agents, cationic surface-active agents, nonionicsurface-active agents, amphoteric surface-active agents and zwitterionicsurface-active agents, and dispersion polymers.

Anionic surface-active agents useful herein include those disclosed inU.S. Pat. No. 5,573,709, incorporated herein by reference. Examplesinclude alkyl and alkyl ether sulfates. Specific examples of alkyl ethersulfates which may be used In this invention are sodium and ammoniumsalts of lauryl sulfate, lauryl ether sulfate, coconut alkyl triethyleneglycol ether sulfate; tallow alkyl triethylene glycol ether sulfate, andtallow alkyl hexaoxyethylene sulfate. Highly preferred alkyl ethersulfates are those comprising a mixture of individual compounds, saidmixture having an average alkyl chain length of from about 12 to about16 carbon atoms and an average degree of ethoxylation of from about 1 toabout 6 moles of ethylene oxide.

Another suitable class of anionic surface-active agents is the alkylsulfuric acid salts. Important examples are the salts of an organicsulfuric acid reaction product of a hydrocarbon of the methane series,including iso-, neo-, and n-paraffins, having about 8 to about 24 carbonatoms, preferably about 12 to about 18 carbon atoms and a sulfonatingagent, for example, sulfur trioxide or oleum, obtained according toknown sulfonation methods, including bleaching and hydrolysis. Preferredare alkali metals and ammonium sulfated C.sub.12-38 n-paraffins.

Additional synthetic anionic surface-active agents include the olefinsulfonates, the beta-alkyloxy alkane sulfonates, and the reactionproducts of fatty acids esterified with isethionic acid and neutralizedwith sodium hydroxide, as well as succinamates. Specific examples ofsuccinamates include disodium N-octadecyl sulfosuccinamate; tetrasodiumN-(1,2-dicarboxyethyl)-N-octadecylsulfosuccinamate; diamyl ester ofsodium sulfosuccinic acid; dihexyl ester of sodium sulfosuccinic acid;dioctyl esters of sodium sulfosuccinic acid.

Preferred anionic surface-active agents for use in the cosmeticallyacceptable composition of this invention include ammonium laurylsulfate, ammonium laureth sulfate, triethylamine lauryl sulfate,triethylamine laureth sulfate, triethanolamine lauryl sulfate,triethanolamine laureth sulfate, monoethanolamine lauryl sulfate,monoethanolamine laureth sulfate, diethanolamine lauryl sulfate,diethanolamine laureth sulfate, lauric monoglyceride sodium sulfate,sodium lauryl sulfate, sodium laureth sulfate, potassium lauryl sulfate,potassium laureth sulfate, sodium lauryl sarcosinate, sodium lauroylsarcosinate, lauryl sarcosine, cocoyl sarcosine, ammonium cocoylsulfate, ammonium lauroyl sulfate, sodium cocoyl sulfate, sodium lauroylsulfate, potassium cocoyl sulfate, potassium lauryl sulfate,triethanolamine lauryl sulfate, triethanolamine lauryl sulfate,monoethanolamine cocoyl sulfate, monoethanolamine lauryl sulfate, sodiumtridecyl benzene sulfonate, and sodium dodecylbenzene sulfonate.

Amphoteric surface-active agents which may be used in the cosmeticallyacceptable composition of this invention include derivatives ofaliphatic secondary and tertiary amines, in which the aliphaticsubstituent contains from about 8 to 18 carbon atoms and an anionicwater solubilizing group e.g., carboxy, sulfonate, sulfate, phosphate,or phosphonate. Representative examples include sodium3-dodecyl-aminopropionate, sodium 3-dodecylaminopropane sulfonate,sodium lauryl sarcosinate, N-alkyltaurines such as the one prepared byreacting dodecylamine with sodium isethionate as described in U.S. Pat.No. 2,658,072, N-higher alkyl aspartic acids as described in U.S. Pat.No. 2,438,091, and the products sold under the trade name MIRANOL, asdescribed in U.S. Pat. No. 2,528,378. Other sarcosinates and sarcosinatederivatives can be found in the CTFA Cosmetic Ingredient Handbook, FifthEdition, 1988, page 42 incorporated herein by reference.

Quaternary ammonium compounds can also be used in the cosmeticallyacceptable composition of this invention as long as they are compatiblein the compositions of the invention, wherein the structure is providedin the CTFA Cosmetic Ingredient Handbook, Fifth Edition, 1988, page 40.Cationic surface-active agents generally include, but are not limited tofatty quaternary ammonium compounds containing from about 8 to about 18carbon atoms. The anion of the quaternary ammonium compound can be acommon ion such as chloride, ethosulfate, methosulfate, acetate,bromide, lactate, nitrate, phosphate, or tosylate and mixtures thereof.The long chain alkyl groups can include additional or replaced carbon orhydrogen atoms or ether linkages. Other substitutions on the quaternarynitrogen can be hydrogen, hydrogen, benzyl or short chain alkyl orhydroxyalkyl groups such as methyl, ethyl, hydroxymethyl orhydroxyethyl, hydroxypropyl or combinations thereof.

Examples of quaternary ammonium compounds include but are not limitedto: Behentrimonium chloride, Cocotrimonium chloride, Cethethyldimoniumbromide, Dibehenyldimonium chloride, Dihydrogenated tallow benzylmoniumchloride, disoyadimonium chloride, Ditallowedimonium chloride,Hydroxycetyl hydroxyethyl dimonium chloride, HydroxyethylBehenamidopropyl dimonium chloride, Hydroxyethyl Cetyldimonium chloride,Hydroxyethyl tallowedimonium chloride, myristalkonium chloride, PEG-2Oleamonium chloride, PEG-5 Stearmonium chloride, PEG-15 cocoylquaternium 4, PEG-2 stearalkonium 4, lauryltrimonium chloride;Quaternium-16; Quaternium-18, lauralkonium chloride, olealkmoniumchloride, cetylpyridinium chloride, Polyquaternium-5, Polyquaternium-6,Polyquaternium-7, Polyquaternium-10, Polyquaternium-22,Polyquaternium-37, Polyquaternium-39, Polyquaternium-47, cetyl trimoniumchloride, dilauryldimonium chloride, cetalkonium chloride,dicetyldimonium chloride, soyatrimonium chloride, stearyl octyl dimoniummethosulfate, and mixtures thereof. Other quaternary ammonium compoundsare listed in the CTFA Cosmetic Ingredient Handbook, First Edition, onpages 41-42, incorporated herein by reference.

The cosmetically acceptable compositions may include long chain fattyamines from about C.sub.10 to C.sub.22 and their derivatives. Specificexamples include dipalmitylamine, lauramidopropyldimethylamine, andstearamidopropyl dimethylamine. The cosmetically acceptable compositionsof this invention may also include fatty alcohols (typically monohydricalcohols), ethoxylated fatty alcohols, and di-tail phospholipids, whichcan be used to stabilize emulsion or dispersion forms of thecosmetically acceptable compositions. They also provide a cosmeticallyacceptable viscosity. Selection of the fatty alcohol is not critical,although those alcohols characterized as having fatty chains of C.sub.10to C.sub.32, preferably C.sub.14 to C.sub.22, which are substantiallysaturated alkanols will generally be employed. Examples include stearylalcohol, cetyl alcohol, cetostearyl alcohol, myristyl alcohol, behenylalcohol, arachidic alcohol, isostearyl alcohol, and isocetyl alcohol.Cetyl alcohol is preferred and may be used alone or in combination withother fatty alcohols, preferably with stearyl alcohol. When used thefatty alcohol is preferably included in the formulations of thisinvention at a concentration within the range from about 1 to about 8weight percent, more preferably about 2 to about 6 weight percent. Thefatty alcohols may also be ethoxylated. Specific examples includecetereth-20, steareth-20, steareth-21, and mixtures thereof.Phospholipids such as phosphatidylserine and phosphatidylcholine, andmixtures thereof may also be included. When used, the fatty alcoholcomponent is included in the formulations at a concentration of about 1to about 10 weight percent, more preferably about 2 to about 7 weightpercent.

Nonionic surface-active agents, which can be used in the cosmeticallyacceptable composition of the present invention, include those broadlydefined as compounds produced by the condensation of alkylene oxidegroups (hydrophilic in nature) with an organic hydrophobic compound,which may be aliphatic or alkyl aromatic in nature. Examples ofpreferred classes of nonionic surface-active agents are: the long chainalkanolamides; the polyethylene oxide condensates of alkyl phenols; thecondensation product of aliphatic alcohols having from about 8 to about18 carbon atoms, in either straight chain or branched chainconfiguration, with ethylene oxide; the long chain tertiary amineoxides; the long chain tertiary phosphine oxides; the long chain dialkylsulfoxides containing one short chain alkyl or hydroxy alkyl radical offrom about 1 to about 3 carbon atoms; and the alkyl polysaccharide (APS)surfactants such as the alkyl polyglycosides; the polyethylene glycol(PEG) glyceryl fatty esters.

Zwitterionic surface-active agents such as betaines can also be usefulin the cosmetically acceptable composition of this invention. Examplesof betaines useful herein include the high alkyl betaines, such as cocodimethyl carboxymethyl betaine, cocoamidopropyl betaine, cocobetaine,lauryl amidopropyl betaine, oleyl betaine, lauryl dimethyl carboxymethylbetaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethylcarboxymethyl betaine, lauryl bis-(2-hydroxyethyl) carboxymethylbetaine, stearyl bis-(2-hydroxypropyl) carboxymethyl betaine, oleyldimethyl gamma-carboxypropyl betaine, and laurylbis-(2-hydroxypropyl)alpha-carboxyethyl betaine. The sulfobetaines maybe represented by coco dimethyl sulfopropyl betaine, stearyl dimethylsulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, laurylbis-(2-hydroxyethyl) sulfopropyl betaine and the like; amidobetaines andamidosulfobetaines, wherein the RCONH(CH₂)₃ radical is attached to thenitrogen atom of the betaine are also useful in this invention.

The anionic, cationic, nonionic, amphoteric or zwitterionicsurface-active agents used in the cosmetically acceptable composition ofthis invention are typically used in an amount from about 0.1 to 50percent by weight, preferably from about 0.5 to about 40 percent byweight, more preferably from about 1 to about 20 percent by weight.

The cosmetically acceptable composition of this invention may includehumectants, which act as hygroscopic agents, increasing the amount ofwater absorbed, held and retained. Suitable humectants for theformulations of this invention include but are not limited to: acetamideMEA, ammonium lactate, chitosan and its derivatives, colloidal oatmeal,galactoarabinan, glucose glutamate, glerecyth-7, glygeryth-12,glycereth-26, glyceryth-31, glycerin, lactamide MEA, lactamide DEA,lactic acid, methyl gluceth-10, methyl gluceth-20, panthenol, propyleneglycol, sorbitol, polyethylene glycol, 1,3-butanediol,1,2,6-hexanetriol, hydrogenated starch hydrolysate, inositol, mannitol,PEG-pentaerythritol ether, polyglyceryl sorbitol, xylitol, sucrose,sodium hyaluronate, sodium PCA, and combinations thereof. Glycerin is aparticularly preferred humectant. The humectant is present in thecomposition at concentrations of from about 0.5 to about 40 percent byweight, preferably from about 0.5 to about 20 percent by weight and morepreferably from about 0.5 to about 12 percent by weight.

The cosmetically acceptable composition of this invention may includepetrolatum or mineral oil components, which when selected will generallybe USP or NF grade. The petrolatum may be white or yellow. The viscosityor consistency grade of petrolatum is not narrowly critical. Petrolatumcan be partially replaced with mixtures of hydrocarbon materials, whichcan be formulated to resemble petrolatum in appearance and consistency.For example, mixtures of petrolatum or mineral oil with different waxesand the like may be combined. Preferred waxes include bayberry wax,candelilla wax, ceresin, jojoba butter, lanolin wax, montan wax,ozokerite, polyglyceryl-3-beeswax, polyglyceryl-6-pentastearate,microcrystalline wax, paraffin wax, isoparaffin, vaseline solidparaffin, squalene, oligomer olefins, beeswax, synthetic candelilla wax,synthetic carnauba, synthetic beeswax and the like may be blendedtogether. Alkylmethyl siloxanes with varying degrees of substitution canbe used to increase water retained by the skin. Siloxanes such asstearyl dimethicone, known as 2503 Wax, C30-45 alkyl methicone, known asAMS-C30 wax, and stearoxytrimethylsilane (and) stearyl alcohol, known as580 Wax, each available from Dow Corning, Midland, Mich., USA.Additional alkyl and phenyl silicones may be employed to enhancemoisturizing properties. Resins such as dimethicone (and)trimethylsiloxysilicate or Cyclomethicone (and) Trimethylsiloxysilicatefluid, may be utilized to enhance film formation of skin care products.When used, the petrolatum, wax or hydrocarbon or oil component isincluded in the formulations at a concentration of about 1 to about 20weight percent, more preferably about 1 to about 12 weight percent. Whenused, the silicone resins can be included from about 0.1 to about 10.0weight percent.

Emollients are defined as agents that help maintain the soft, smooth,and pliable appearance of skin. Emollients function by their ability toremain on the skin surface or in the stratum corneum. The cosmeticallyacceptable composition of this invention may include fatty esteremollients, which are listed in the International Cosmetic IngredientDictionary, Eighth Edition, 2000, p. 1768 to 1773. Specific examples ofsuitable fatty esters for use in the formulation of this inventioninclude isopropyl myristate, isopropyl palmitate, caprylic/caprictriglycerides, cetyl lactate, cetyl palmitate, hydrogenated castor oil,glyceryl esters, hydroxyacetyl isostearate, hydroxy cetyl phosphate,isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate,PPG-5-Ceteth-20, 2-ethylhexyl isononoate, 2-ethylhexyl stearate,C.sub.12 to C.sub.16 fatty alcohol lactate, isopropyl lanolate,2-ethyl-hexyl salicylate, and mixtures thereof. The presently preferredfatty esters are isopropyl myristate, isopropyl palmitate,PPG-5-Ceteth-20, and caprylic/capric triglycerides. When used the fattyester emollient is preferably included in the formulations of thisinvention at a concentration of about 1 to about 8 weight percent, morepreferably about 2 to about 5 weight percent.

The compositions of this invention may also include silicone compounds.Preferably, the viscosity of the silicone component is from about 0.5 toabout 12,500 cps. Examples of suitable materials aredimethylpolysiloxane, diethylpolysiloxane,dimethylpolysiloxane-diphenylpolysiloxane, cyclomethicone,trimethylpolysiloxane, diphenylpolysiloxane, and mixtures thereof.Dimethicone, a dimethylpolysiloxane end blocked with trimethyl units, isone preferred example. Dimethicone having a viscosity between 50 and1,000 cps is particularly preferred. When used, the silicone oils arepreferably included in the formulations of this invention at aconcentration of 0.1 to 5 weight percent, more preferably 1 to 2 weightpercent.

The cosmetically acceptable compositions of this invention may includevolatile and non-volatile silicone oils or fluids. The siliconecompounds can be either linear or cyclic polydimethylsiloxanes with aviscosity from about 0.5 to about 100 centistokes. The most preferredlinear polydimethylsiloxane compounds have a range from about 0.5 toabout 50 centistokes. One example of a linear, low molecular weight,volatile polydimethylsiloxane is octamethyltrisiloxane-200 fluid havinga viscosity of about 1 centistoke. When used, the silicone oils arepreferably included in the formulations of this invention at aconcentration of 0.1 to 30 weight percent, more preferably 1 to 20weight percent.

The cosmetically acceptable compositions of this invention may includevolatile, cyclic, low molecular weight polydimethylsiloxanes(cyclomethicones). The preferred cyclic volatile siloxanes can bepolydimethyl cyclosiloxanes having an average repeat unit of 4 to 6, anda viscosity from about 2.0 to about 7.0 centistokes, and mixturesthereof. Preferred cyclomethicones are available from Dow Corning,Midland, Mich., and from General Electric, Waterford, N.Y., USA. Whenused, the silicone oils are preferably included in the formulations ofthis invention at a concentration of 0.1 to 30 weight percent, morepreferably 1 to 20 weight percent.

Silicone surfactants or emulsifiers with polyoxyethylene orpolyoxypropylene side chains may also be used in compositions of thecurrent invention. Preferred examples include dimethicone copolyols and5225C Formulation Aids, available from Dow Corning, Midland, Mich., USAand Silicone SF-1528, available from General Electric, Waterford, N.Y.,USA. The side chains may also include alkyl groups such as lauryl orcetyl. Preferred are lauryl methicone copolyol. 5200 Formulation Aid,and cetyl dimethicone copolyol, known as Abil EM-90, available fromGoldschmidt Chemical Corporation, Hopewell, Va. Also preferred is lauryldimethicone, known as Belsil LDM 3107 VP, available from Wacker-Chemie,Munchen, Germany. When used, the silicone surfactants are preferablyincluded in the formulations of this invention at a concentration of 0.1to 30 weight percent, more preferably 1 to 15 weight percent. Aminefunctional silicones and emulsions may be utilized in the presentinvention. Preferred examples include Dow Corning 8220, Dow Corning 939,Dow Corning 949, Dow Corning 2-8194, all available from Dow Corning,Midland, Mich., USA. Also preferred is Silicone SM 253 available fromGeneral Electric, Waterford, N.Y., USA. When used, the amine functionalsilicones are preferably included in the formulations of this inventionat a concentration of 0.1 to 5 weight percent, more preferably 0.1 to2.0 weight percent.

The cosmetically acceptable compositions of this invention may includevolatile hydrocarbon oils. The volatile hydrocarbon comprises from aboutC.sub.6 to C.sub.22 atoms. A preferred volatile hydrocarbon is analiphatic hydrocarbon having a chain length from about C.sub.6 toC.sub.16 carbon atoms. An example of such compound includesisohexadecane, under the trade name Permethyl 101A, available fromPresperse, South Plainfield, N.J., USA. Another example of a preferredvolatile hydrocarbon is C.sub.12 to C.sub.14 isoparaffin, under thetrade name Isopar M, available from Exxon, Baytown, Tex., USA. Whenused, the volatile hydrocarbons are preferably included in theformulations of this invention at a concentration of 0.1 to 30 weightpercent, more preferably 1 to 20 weight percent.

The cosmetically acceptable compositions of this invention may includecationic and ampholytic conditioning polymers. Examples of such include,but are not limited to those listed by the International CosmeticIngredient Dictionary published by the Cosmetic, Toiletry, and FragranceAssociation (CTFA), 1101 17 Street, N.W., Suite 300, Washington, D.C.20036. General examples include quaternary derivatives of celluloseethers, quaternary derivatives of guar, homopolymers and copolymers ofDADMAC, homopolymers and copolymers of MAPTAC and quaternary derivativesof starches. Specific examples, using the CTFA designation, include, butare not limited to Polyquaternium-10, Guar hydroxypropyltrimoniumchloride, Starch hydroxypropyltrimonium chloride, Polyquaternium-4,Polyquaternium-5, Polyquaternium-6, Polyquaternium-7, Polyquaternium-14,Polyquaternium-15, Polyquaternium-22, Polyquaternium-24,Polyquaternium-28, Polyquaternium-32, Polyquaternium-33,Polyquaternium-36, Polyquaternium-37, Polyquaternium-39,Polyquaternium-45, Polyquaternium-47 andpolymethacrylamidopropyltrimonium chloride, and mixtures thereof. Whenused, the conditioning polymers are preferably included in thecosmetically acceptable composition of this invention at a concentrationof from 0.1 to 10 weight percent, preferably from 0.2 to 6 weightpercent and most preferably from 0.2 to 5 weight percent.

The cosmetically acceptable composition of this invention may includeone or more rheological modifiers. The rheological modifiers that can beused in this invention include high molecular weight crosslinkedhomopolymers of acrylic acid, and Acrylates/C10-30 Alkyl AcrylateCrosspolymer, such as the Carbopol and Pemulen series, both availablefrom B.F. Goodrich, Akron, Ohio, USA; anionic acrylate polymers such asSalcare and cationic acrylate polymers such as Salcare SC96, availablefrom Ciba Specialties, High Point, N.C., USA; Acrylamidopropyltrimoniumchloride/acrylamide; Hydroxyethyl methacrylates polymers, Steareth-10Allyl Ether/Acrylate Copolymer; Acrylates/Beheneth-25 MetacrylateCopolymer, known as Aculyn, available from International Specialties,Wayne, N.J., USA; Glyceryl Polymethacrylate, Acrylates/Steareth-20Methacrylate Copolymer; bentonite; gums such as alginates, carageenans,gum acacia, gum arabic, gum ghatti, gum karaya, gum tragacanth, guargum; guar hydroxypropyltrimonium chloride, xanthan gum or gellan gum;cellulose derivatives such as sodium carboxymethyl cellulose,hydroxyethyl cellulose, hydroxymethyl carboxyethyl cellulose,hydroxymethyl carboxypropyl cellulose, ethyl cellulose, sulfatedcellulose, hydroxypropyl cellulose, methyl cellulose,hydroxypropylmethyl cellulose, microcrystalline cellulose; agar; pectin;gelatin; starch and its derivatives; chitosan and its derivatives suchas hydroxyethyl chitosan; polyvinyl alcohol, PVM/MA copolymer, PVM/MAdecadiene crosspolymer, poly(ethylene oxide) based thickeners, sodiumcarbomer, and mixtures thereof. When used, the rheology modifiers arepreferably included in the cosmetically acceptable composition of thisinvention at a concentration of from 0.01 to 12 weight percent,preferably from 0.05 to 10 weight percent and most preferably from 0.1to 6 weight percent.

The cosmetically acceptable composition of this invention may includeone or more antioxidants, which include, but are not limited to ascorbicacid, BHT, BHA, erythorbic acid, bisulfite, thioglycolate, tocopherol,sodium metabisulfite, vitamin E acetate, and ascorbyl palmitate. Theanti oxidants will be present at from 0.01 to 20 weight percent,preferably 0.5 to 10 weight percent and most preferably from 1.0 to 5.0weight percent of the cosmetically acceptable composition.

The cosmetically acceptable composition of this invention may includeone or more sunscreen active agents. Examples of sunscreen active agentsinclude, but are not limited to octyl methoxycinnamate (ethylhexylp-methoxycinnamate), octyl salicylate oxybenzone (benzophenone-3),benzophenone-4, menthyl anthranilate, dioxybenzone, aminobenzoic acid,amyl dimethyl PABA, diethanolamine p-methoxy cinnamate, ethyl4-bis(hydroxypropyl)aminobenzoate, 2-ethylhexyl1-2-cyano-3,3-diphenylacrylate, homomethyl salicylate, glycerylaminobenzoate, dihydroxyacetone, octyl dimethyl PABA,2-phenylbenzimidazole-5-sulfonic acid, triethanolamine salicylate, zincoxide, and titanium oxide, and mixtures thereof. The amount of sunscreenused in the cosmetically acceptable composition of this invention willvary depending on the specific UV absorption wavelength(s) of thespecific sunscreen active(s) used and can be from 0.1 to 10 percent byweight, from 2 to 8 percent by weight.

The cosmetically acceptable composition of this invention may includeone or more preservatives. Example of preservatives, which may be usedinclude, but are not limited to 1,2-dibromo-2,4-dicyano butane(Methyldibromo Glutaronitrile, known as MERGUARD. Nalco ChemicalCompany, Naperville, Ill., USA), benzyl alcohol, imidazolidinyl urea,1,3-bis(hydroxymethyl)-5,5-dimethyl-2,3-imidazolidinedione (e.g., DMDMHydantoin, known as GLYDANT, Lonza, Fairlawn, N.J., USA,methylchloroisothiazolinone and methylisothiazolinone (e.g., Kathon,Rohm & Haas Co., Philadelphia, Pa., USA), methyl paraben, propylparaben, phenoxyethanol, and sodium benzoate, and mixtures thereof.

The cosmetically acceptable composition of this invention may includeany other ingredient by normally used in cosmetics. Examples of suchingredients include, but are not limited to buffering agents, fragranceingredients, chelating agents, color additives or dyestuffs which canserve to color the composition itself or keratin, sequestering agents,softeners, foam synergistic agents, foam stabilizers, sun filters andpeptizing agents.

The surface of pigments, such titanium dioxide, zinc oxide, talc,calcium carbonate or kaolin, can be treated with the unsaturatedquaternary ammonium compounds described herein and then used in thecosmetically acceptable composition of this invention. The treatedpigments are then more effective as sunscreen actives and for use incolor cosmetics such as make up and mascara.

The cosmetically acceptable composition of this invention can bepresented in various forms. Examples of such forms include, but are notlimited a solution, liquid, cream, emulsion, dispersion, gel, thickeninglotion.

The cosmetically acceptable composition of this invention may containwater and also any cosmetically acceptable solvent. Examples ofacceptable solvents include, but are not limited to monoalcohols, suchas alkanols having 1 to 8 carbon atoms (like ethanol, isopropanol,benzyl alcohol and phenylethyl alcohol) polyalcohols, such as alkyleneglycols (like glycerin, ethylene glycol and propylene glycol) and glycolethers, such as mono-, di- and tri-ethylene glycol monoalkyl ethers, forexample ethylene glycol monomethyl ether and diethylene glycolmonomethyl ether, used singly or in a mixture from 0.1 to 70 percent byweight, relative to the weight of the total composition.

The cosmetically acceptable composition of this invention can also bepackaged as an aerosol, in which case it can be applied either in theform of an aerosol spray or in the form of an aerosol foam. As thepropellant gas for these aerosols, it is possible to use, in particular,dimethyl ether, carbon dioxide, nitrogen, nitrous oxide, air andvolatile hydrocarbons, such as butane, isobutane, and propane.

The cosmetically acceptable composition of this invention also cancontain electrolytes, such as aluminum chlorohydrate, alkali metalsalts, e.g., sodium, potassium or lithium salts, these salts preferablybeing halides, such as the chloride or bromide, and the sulfate, orsalts with organic acids, such as the acetates or lactates, and alsoalkaline earth metal salts, preferably the carbonates, silicates,nitrates, acetates, gluconates, pantothenates and lactates of calcium,magnesium and strontium.

Compositions for treating skin include leave-on or rinse-off skin careproducts such as lotions, hand/body creams, shaving gels or shavingcreams, body washes, sunscreens, liquid soaps, deodorants,antiperspirants, suntan lotions, after sun gels, bubble baths, hand ormechanical dishwashing compositions, and the like. In addition to thepolymer, skin care compositions may include components conventionallyused in skin care formulations. Such components include for example; (a)humectants, (b) petrolatum or mineral oil, (c) fatty alcohols, (d) fattyester emollients, (e) silicone oils or fluids, and (f) preservatives.These components must in general be safe for application to the humanskin and must be compatible with the other components of theformulation. Selection of these components is generally within the skillof the art. The skin care compositions may also contain otherconventional additives employed in cosmetic skin care formulations. Suchadditives include aesthetic enhancers, fragrance oils, dyes andmedicaments such as menthol and the like.

The skin care compositions of this invention may be prepared asoil-in-water, water-in-oil emulsions, triple emulsions, or dispersions.

Preferred oil-in-water emulsions are prepared by first forming anaqueous mixture of the water-soluble components, e.g. unsaturatedquaternary ammonium compounds, humectants, water-soluble preservatives,followed by adding water-insoluble components. The water-insolublecomponents include the emulsifier, water-insoluble preservatives,petrolatum or mineral oil component, fatty alcohol component, fattyester emollient, and silicone oil component. The input of mixing energywill be high and will be maintained for a time sufficient to form awater-in-oil emulsion having a smooth appearance (indicating thepresence of relatively small micelles in the emulsion). Preferreddispersions are generally prepared by forming an aqueous mixture of thewater-soluble components, followed by addition of thickener withsuspension power for water-insoluble materials.

Compositions for treating hair include bath preparations such as bubblebaths, soaps, and oils, shampoos, conditioners, hair bleaches, haircoloring preparations, temporary and permanent hair colors, colorconditioners, hair lighteners, coloring and non-coloring hair rinses,hair tints, hair wave sets, permanent waves, curling, hairstraighteners, hair grooming aids, hair tonics, hair dressings andoxidative products. The dispersion polymers may also be utilized instyling type leave-in products such as gels, mousses, spritzes, stylingcreams, styling waxes, pomades, balms, and the like, either alone or incombination with other polymers or structuring agents in order toprovide control and hair manageability with a clean, natural, non-stickyfeel.

Hair care compositions of this invention give slippery feel and that canbe easily rinsed from the hair due to the presence of the dispersionpolymer, volatile silicones, other polymers, surfactants or othercompounds that may alter the deposition of materials upon the hair.

In the case of cleansing formulations such as a shampoo for washing thehair, or a liquid hand soap, or shower gel for washing the skin, thecompositions contain anionic, cationic, nonionic, zwitterionic oramphoteric surface-active agents typically in an amount from about 3 toabout 50 percent by weight, preferably from about 3 to about 20 percent,and their pH is general in the range from about 3 to about 10.

Preferred shampoos of this invention contain combinations of anionicsurfactants with zwitterionic surfactants and/or amphoteric surfactants.Especially preferred shampoos contain from about 0 to about 16 percentactive of alkyl sulfates, from 0 to about 50 weight percent ofethoxylated alkyl sulfates, and from 0 to about 50 weight percent ofoptional surface-active agents selected from the nonionic, amphoteric,and zwitterionic surface-active agents, with at least 5 weight percentof either alkyl sulfate, ethoxylated alkyl sulfate, or a mixturethereof, and a total surfactant level of from about 10 weight to about25 percent.

The shampoo for washing hair also can contain other conditioningadditives such as silicones and conditioning polymers typically used inshampoos. U.S. Pat. No. 5,573,709 provides a list of non-volatilesilicone conditioning agents that can be used in shampoos. Theconditioning polymers for use with the present invention are listed inthe Cosmetic, Toiletries and Fragrance Associations (CTFA) dictionary.Specific examples include the Polyquaterniums (example Polyquaternium-1to Polyquaternium-50), Guar Hydroxypropyl Trimonium Chloride, StarchHydroxypropyl Trimonium Chloride and Polymethacrylamidopropyl TrimoniumChloride.

Other preferred embodiments consist of use in the form of a rinsinglotion to be applied mainly before or after shampooing. These lotionstypically are aqueous or aqueous-alcoholic solutions, emulsions,thickened lotions or gels. If the compositions are presented in the formof an emulsion, they can be nonionic, anionic or cationic. The nonionicemulsions consist mainly of a mixture of oil and/or a fatty alcohol witha polyoxyethyleneated alcohol, such as polyoxyethyleneated stearyl orcetyl/stearyl alcohol, and cationic surface-active agents can be addedto these compositions. The anionic emulsions are formed essentially fromsoap.

If the compositions are presented in the form of a thickened lotion or agel, they contain thickeners in the presence or absence of a solvent.The thickeners which can be used are especially resins, Carbopol-typeacrylic acid thickeners available from B.F. Goodrich; xanthan gums;sodium alginates; gum arabic; cellulose derivatives and poly-(ethyleneoxide) based thickeners, and it is also possible to achieve thickeningby means of a mixture of polyethylene glycol stearate or distearate orby means of a mixture of a phosphoric acid ester and an amide. Theconcentration of thickener is generally 0.05 to 15 percent by weight. Ifthe compositions are presented in the form of a styling lotion, shapinglotion, or setting lotion, they generally comprise, in aqueous,alcoholic or aqueous-alcoholic solution, the ampholyte polymers definedabove.

In the case of hair fixatives, the composition may also contain one ormore additional hair fixative polymers. When present, the additionalhair fixative polymers are present in a total amount of from about 0.25to about 10 percent by weight. The additional hair fixative resin can beselected from the following group as long as it is compatible with agiven dispersion polymer: acrylamide copolymer, acrylamide/sodiumacrylate copolymer, acrylate/ammonium methacrylate copolymer, anacrylate copolymer, an acrylic/acrylate copolymer, adipicacid/dimethylaminohydroxypropyl diethylenetriamine copolymer, adipicacid/epoxypropyl diethylenetriamine copolymer, allyl stearate/VAcopolymer, aminoethylacrylate phosphate/acrylate copolymer, an ammoniumacrylate copolymer, an ammonium vinyl acetate/acrylate copolymer, an AMPacrylate/diacetoneacrylamide copolymer, an AMPDacrylate/diacetoneacrylamide copolymer, butyl ester of ethylene/maleicanhydride copolymer, butyl ester of PVM/MA copolymer, calcium/sodiumPVM/MA copolymer, corn starch/acrylamide/sodium acrylate copolymer,diethylene glycolamine/epichlorohydrin/piperazine-copolymer,dodecanedioic acid/cetearyl alcohol/glycol copolymer, ethyl ester ofPVM/MA copolymer, isopropyl ester of PVM/MA copolymer, karaya gum, amethacryloyl ethyl betaine/methacrylate copolymer, anoctylacrylamide/acrylate/butylaminoethyl methacrylate copolymer, anoctylacrylamide/acrylate copolymer, phthalic anhydride/glycerin/glycidyldecanoate copolymer, a phthalic/trimellitic/glycol copolymer,polyacrylamide, polyacrylamidomethylpropane sulfonic acid, polybutyleneterephthalate, polyethylacrylate, polyethylene, polyquaternium-1,polyquaternium-2, polyquaternium-4, polyquaternium-5, polyquaternium-6,polyquaternium-7, polyquaternium-8, polyquaternium-9, polyquaternium-10,polyquaternium-11, polyquaternium-12, polyquaternium-13,polyquaternium-14, polyquaternium-15, polyquaternium-39,polyquaternium-47, polyvinyl acetate, polyvinyl butyral, polyvinylimidazolinium acetate, polyvinyl methyl ether, PVM/MA copolymer, PVP,PVP/dimethylaminoethylmethacrylate copolymer, PVP/eicosene copolymer,PVP/ethyl methacrylate/methacrylic acid copolymer, PVP/hexadecenecopolymer, PVP/VA copolymer, PVP/vinyl acetate/itaconic acid copolymer,shellac, sodium acrylates copolymer, sodium acrylates/Acrylnitrogenscopolymer, sodium acrylate/vinyl alcohol copolymer, sodium carrageenan,starch diethylaminoethyl ether, stearylvinyl ether/maleic anhydridecopolymer, sucrose benzoate/sucrose acetate isobutyrate/butyl benzylphthalate copolymer, sucrose benzoate/sucrose acetate isobutyrate/butylbenzyl phthalate/methyl methacrylate copolymer, sucrose benzoate/sucroseacetate isobutyrate copolymer, a vinyl acetate/crotonate copolymer,vinyl acetate/crotonic acid copolymer, vinyl acetate/crotonicacid/methacryloxybenzophenone-1 copolymer, vinyl acetate/crotonicacid/vinyl neodecanoate copolymer, and mixtures thereof. Syntheticpolymers used for creating styling aids are described in “The History ofPolymers in Haircare,” Cosmetics and Toiletries, 103 (1988),incorporated herein by reference. Other synthetic polymers that may beused with the present invention can be referenced in the CTFADictionary, Fifth Edition, 2000, incorporated herein by reference.

The cosmetic compositions of this invention may be formulated in a widevariety of form, for non-limited example, including a solution, asuspension, an emulsion, a paste, an ointment, a gel, a cream, a lotion,a powder, a soap, a surfactant-containing cleanser, an oil, a powderfoundation, an emulsion foundation, a wax foundation and a spray. Indetail, the cosmetic composition of the present invention can beprovided in a form of skin softener (skin lotion), astringent lotion,nutrient emulsion (milk lotion), nutrient cream, message cream, essence,eye cream, cleansing cream, cleansing foam, cleansing water, facialpack, spray or powder.

The cosmetically acceptable carrier contained in the present cosmeticcomposition, may be varied depending on the type of the formulation. Forexample, the formulation of ointment, pastes, creams or gels maycomprise animal and vegetable fats, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones,bentonite, silica, talc, zinc oxide or mixtures of these ingredients.

In the formulation of powder or spray, it may comprise lactose, talc,silica, aluminum hydroxide, calcium silicate, polyamide powder andmixtures of these ingredients. Spray may additionally comprise thecustomary propellants, for example, chlorofluorohydrocarbons, propane,butane, diethyl ether, or dimethyl ether.

The formulation of solution and emulsion may comprise solvent,solubilizer and emulsifier, for example water, ethanol, isopropanol,ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,propylene glycol, 1,3-butyleneglycol, oils, in particular cottonseedoil, groundnut oil, maize germ oil, olive oil, castor oil and sesameseed oil, glycerol fatty esters, polyethylene glycol and fatty acidesters of sorbitan or mixtures of these ingredients.

The formulation of suspension may comprise liquid diluents, for examplewater, ethanol or propylene glycol, suspending agents, for exampleethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters andpolyoxyethylene sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar and tragacanth or mixtures of theseingredients.

The formulation of cleansing compositions with surfactant may comprisealiphatic alcohol sulfate, aliphatic alcohol ether sulfate,sulfosucinnate monoester, isethionate, imidazolium derivatives, methyltaurate, sarcosinate, fatty acid amide ether sulfate, alkyl amidobetaine, aliphatic alcohol, fatty acid glyceride, fatty aciddiethanolamide, vegetable oil, lanoline derivatives, ethoxylatedglycerol fatty acid ester or mixtures of these ingredients.

Additional antioxidant ingredients and compositions can be selectedfrom, but not limited to, Ascorbic acid, Ascorbic acid derivatives,Glucosamine ascorbate, Arginine ascorbate, Lysine ascorbate, Glutathioneascorbate, Nicotinamide ascorbate, Niacin ascorbate, Allantoinascorbate, Creatine ascorbate, Creatinine ascorbate, Chondroitinascorbate, Chitosan ascorbate, DNA Ascorbate, Carnosine ascorbate,Vitamin E, various Vitamin E derivatives, Tocotrienol, Rutin, Quercetin,Hesperedin (Citrus sinensis), Diosmin (Citrus sinensis), Mangiferin(Mangifera indica), Mangostin (Garcinia mangostana), Cyanidin (Vacciniummyrtillus), Astaxanthin (Haematococcus algae), Lutein (Tagetes patula),Lycopene (Lycopersicum esculentum), Resveratrol (Polygonum cuspidatum),Tetrahydrocurcumin (Curcuma longa), Rosmarinic acid (Rosmarinusofficinalis), Hypericin (Hypericum perforatum), Ellagic acid (Punicagranatum), Chlorogenic acid (Vaccinium vulgaris), Oleuropein (Oleaeuropaea), .alpha.-Lipoic acid, Niacinamide lipoate, Glutathione,Andrographolide (Andrographis paniculata), Carnosine, Niacinamide,Potentilla erecta extract, Polyphenols, Grapeseed extract, Pycnogenol(Pine Bark extract), Pyridoxine, Magnolol, Honokiol, Paeonol,Resacetophenone, Quinacetophenone, arbutin, kojic acid, and combinationsthereof.

The blood micro-circulation improvement ingredients and compositions canbe selected from, but not limited to, Horse Chestnut Extract (Aesculushippocastanum extract)), Esculin, Escin, Yohimbine, Capsicum Oleoresin,Capsaicin, Niacin, Niacin Esters, Methyl Nicotinate, Benzyl Nicotinate,Ruscogenins (Butchers Broom extract; Ruscus aculeatus extract),Diosgenin (Trigonella foenumgraecum, Fenugreek), Emblica extract(Phyllanthus emblica extract), Asiaticoside (Centella asiatica extract),Boswellia Extract (Boswellia serrata), Ginger Root Extract (ZingiberOfficianalis), Piperine, Vitamin K, Melilot (Melilotus officinalisextract), Glycyrrhetinic acid, Ursolic acid, Sericoside (Terminaliasericea extract), Darutoside (Siegesbeckia orientalis extract), Amnivisnaga extract, extract of Red Vine (Vitis Vinifera) leaves, apigenin,phytosan, luteolin, and combinations thereof.

The anti-inflammatory ingredients or compositions can be selected from,but not limited to, at least one antioxidant class of Cyclo-oxygenase(for example, COX-1 or COX-2) or Lipoxygenase (for example, LOX-5)enzyme inhibitors such as Ascorbic acid, Ascorbic acid derivatives,Vitamin E, Vitamin E derivatives, Tocotrienol, Rutin, Quercetin,Hesperedin (Citrus sinensis), Diosmin (Citrus sinensis), Mangiferin(Mangifera indica), Mangostin (Garcinia mangostana), Cyanidin (Vacciniummyrtillus), Astaxanthin (Haematococcus algae), Lutein (Tagetes patula),Lycopene (Lycopersicum esculentum), Resveratrol (Polygonum cuspidatum),Tetrahydrocurcumin (Curcuma longa), Rosmarinic acid (Rosmarinusofficinalis), Hypericin (Hypericum perforatum), Ellagic acid (Punicagranatum), Chlorogenic acid (Vaccinium vulgaris), Oleuropein (Oleaeuropaea), alpha-Lipoic acid, Glutathione, Andrographolide, Grapeseedextract, Green Tea Extract, Polyphenols, Pycnogenol (Pine Bark extract),White Tea extract, Black Tea extract, (Andrographis paniculata),Carnosine, Niacinamide, and Emblica extract. Anti-inflammatorycomposition can additionally be selected from, but not limited to, HorseChestnut Extract (Aesculus hippocastanum extract)), Esculin, Escin,Yohimbine, Capsicum Oleoresin, Capsaicin, Niacin, Niacin Esters, MethylNicotinate, Benzyl Nicotinate, Ruscogenins (Butchers Broom extract;Ruscus aculeatus extract), Diosgenin (Trigonella foenumgraecum,Fenugreek), Emblica extract (Phyllanthus emblica extract), Asiaticoside(Centella asiatica extract), Boswellia Extract (Boswellia serrata),Sericoside, Visnadine, Thiocolchicoside, Grapeseed Extract, Ginger RootExtract (Zingiber Officianalis), Piperine, Vitamin K, Melilot (Melilotusofficinalis extract), Glycyrrhetinic acid, Ursolic acid, Sericoside(Terminalia sericea extract), Darutoside (Siegesbeckia orientalisextract), Amni visnaga extract, extract of Red Vine (Vitis-Vinifera)leaves, apigenin, phytosan, luteolin, and combinations thereof.

Certain divalent and polyvalent metal ions can also be present in thecompositions of the present invention. The examples of such metal ionsinclude zinc, copper, manganese, vanadium, chromium, cobalt, and iron.

The present invention also provides a pharmaceutical composition thatcomprises a carrier and, as active ingredient, a compound of the generalformula (VII) as defined above.

A pharmaceutically acceptable carrier may be any material with which theactive ingredient is formulated to facilitate administration. A carriermay be a solid or a liquid, including a material that is normallygaseous but which has been compressed to form a liquid, and any of thecarriers normally used in formulating pharmaceutical compositions may beused. Preferably, compositions according to the invention contain 0.5 to95% by weight of active ingredient.

The compounds of general formula (VII) can be formulated as, forexample, tablets, capsules, suppositories or solutions. Theseformulations can be produced by known methods using conventional solidcarriers such as, for example, lactose, starch or talcum or liquidcarriers such as, for example, water, fatty oils or liquid paraffins.Other carriers which may be used include materials derived from animalor vegetable proteins, such as the gelatins, dextrins and soy, wheat andpsyllium seed proteins; gums such as acacia, guar, agar, and xanthan;polysaccharides; alginates; carboxymethylcelluloses; carrageenans;dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone;polypeptide/protein or polysaccharide complexes such as gelatin-acaciacomplexes; sugars such as mannitol, dextrose, galactose and trehalose;cyclic sugars such as cyclodextrin; inorganic salts such as sodiumphosphate, sodium chloride and aluminium silicates.

Auxiliary components such as tablet disintegrants, solubilisers,preservatives, antioxidants, surfactants, viscosity enhancers, colouringagents, flavouring agents, pH modifiers, sweeteners or taste-maskingagents may also be incorporated into the composition. Suitable colouringagents include red, black and yellow iron oxides and FD & C dyes such asFD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard.Suitable flavouring agents include mint, raspberry, liquorice, orange,lemon, grapefruit, caramel, vanilla, cherry and grape flavours andcombinations of these. Suitable pH modifiers include citric acid,tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.Suitable sweeteners include aspartame, acesulfame K and thaumatin.Suitable taste-masking agents include sodium bicarbonate, ion-exchangeresins, cyclodextrin inclusion compounds, adsorbates ormicroencapsulated actives.

For treatment of and prophylaxis against coccidiosis and relatedparasites, for instance, in poultry, especially in chickens, ducks,geese and turkeys, 0.1 to 100 ppm, preferably 0.5 to 100 ppm of theactive compound may be mixed into an appropriate, edible material, suchas nutritious food. If desired, the amounts applied can be increased,especially if the active compound is well tolerated by the recipient.Accordingly, the active compound can be applied with the drinking water.

For the treatment of a single animal, for instance, for the treatment ofcoccidiosis in mammals or toxoplasmosis, amounts of 0.5 to 100 mg/kgbody weight active compound are preferably administered daily to obtainthe desired results. Nevertheless, it may be necessary from time to timeto depart from the amounts mentioned above, depending on the body weightof the experimental animal, the method of application, the animalspecies and its individual reaction to the drug or the kind offormulation or the time or interval in which the drug is applied. Inspecial cases, it may be sufficient to use less than the minimum amountgiven above, whilst in other cases the maximum dose may have to beexceeded. For a larger dose, it may be advisable to divide the dose intoseveral smaller single doses.

The present invention also includes a compound of the general formula(VII) as defined above for use in the treatment and/or prophylaxis of adisease caused by infection with a parasite of the genus Plasmodium anduse of a compound of the general formula (VII) as defined above for themanufacture of a medicament for the treatment and/or prophylaxis of adisease caused by infection with a parasite of the genus Plasmodium.

The invention also provides a method for treating a disease caused byinfection with a parasite other than an organism of the genus Plasmodiumthat comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of the general formula(VII) as first defined above. Preferably, the parasite is an organism ofthe genus Neospora or the genus Eimeria. A method for treating a diseasecaused by infection with a parasite of the genus Plasmodium is alsoprovided which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a novel compound of thegeneral formula I as defined above.

EXAMPLES

All quantities are in weight percent amounts. The examples do not limitthe scope of the present invention. Nomenclature of some compounds hasbeen abbreviated.

Example 1 Preparation of N-(Decanoyl)-Glutaminyl-Glutamine Amide(Formula IV)

Procedure. An equimolar amount of glutaminyl-glutamine amide, sodiumbicarbonate, and decanoyl chloride are reacted in water. The pH isadjusted to 5.5 to 6.5, whereupon compound of formula (IV) crystallizesout, which is then filtered, washed with water, and dried.

Example 2 Preparation of Glutaminyl-Glutamine Amide (Formula V)

Procedure. Glutaminyl-glutamine amide (formula V) is obtained bystandard peptide synthesis.

Example 3 Preparation of N-Acetyl-Glutamyl-Glutamic Acid (Formula VIII)

Procedure. An equimolar amount of glutamyl-glutamic acid, sodiumbicarbonate, and acetyl chloride are reacted in water. The pH isadjusted to 5.5 to 6.5, whereupon compound of formula (VIII)crystallizes out, which is then filtered, washed with water, and dried.

Example 4 Skin Whitening and Anti-Wrinkle Serum

Ingredients. (1) Ethyl Lactate 24.0 (2) Polyalkyleneoxy Polyamide 0.5(3) Compound of formula (VII) 1.0 (4) PEG-670.0 (5) Resacetophenone 4.0(6) Preservatives 0.5. Procedure. Make serum base by mixing (1) to (3)at room temperature or slight heating. Pre-mix (4) to (6) to a clearsolution and add to main batch with mixing. The product has serum likeappearance.

Example 5 Anti-Acne and Facial Oil Control Cream

Ingredients. (1) Deionized water 79.5 (2) Cetearyl alcohol (and) dicetylphosphate (and) Ceteth-10 phosphate 5.0 (3) Cetyl alcohol 2.0 (4)Glyceryl stearate (and) PEG-100 stearate 4.0 (5) Ethyl Lactate 5.0 (6)Compound of formula (IV) 3.0 (7)N-(Deoxyaloesinylideneamino)-4-hydroxyphenylacetic acid 1.0 (8)Preservatives 0.5. Procedure. Mix 1 to 5 and heat to 75-80.degree. C.Adjust pH to 4.0 4.5. Cool to 35-40 C with mixing. Add 6 to 8 withmixing. Adjust pH to 4.0-4.5, if necessary. An off-white cream isobtained.

Example 6 Skin Abrasion Treatment Cream

Ingredients. (1) Water 53.9 (2) Dicetyl Phosphate (and) Ceteth-10Phosphate 5.0 (3) Glyceryl Stearate (and) PEG-100 Stearate 4.0 (4)Phenoxyethanol 0.7 (5) Chlorphenesin 0.3 (60) Titanium Dioxide 0.2 (7)Sodium Hydroxide 0.5 (8) Magnolol 0.2 (9) Boswellia Serrata 0.5 (10)Cetyl Dimethicone 1.5 (11) Tetrahydrocurcuminoids 0.5 (12) Shea butter2.0 (13) Ximenia oil 1.0 (14) Water 5.0 (15) Niacinamide Lactate 1.0(16) Niacinamide Hydroxycitrate 3.1 (17) Compound of formula (V) 2.5(18) Paeonol 1.5 (19) Carnosine 0.1 (20) Cyclomethicone, DimethiconeCrosspolymer 2.0 (21) Arbutin 0.5 (22) Polysorbate-20 2.0 (23) EthylLactate 12.0. Procedure. Mix (1) to (13) and heat at 70 to 80 C tillhomogenous. Cool to 40 to 50 C. Premix (14) to (16) and add to batchwith mixing. Mix (17) to (23) to a clear solution and add to main batchmix. Cool to room temperature. An off-white cream is obtained.

Example 7 Acne Cream

Ingredients. (1) Water 53.9 (2) Dicetyl Phosphate (and) Ceteth-10Phosphate 5.0 (3) Glyceryl Stearate (and) PEG-100 Stearate 4.0 (4)Phenoxyethanol 0.7 (5) Chlorphenesin 0.3 (60) Titanium Dioxide 0.2 (7)Sodium Hydroxide 0.5 (8) Magnolol 0.2 (9) Boswellia Serrata 0.5 (10)Cetyl Dimethicone 1.5 (11) Tetrahydrocurcuminoids 0.5 (12) Shea butter2.0 (13) Ximenia oil 1.0 (14) Niacinamide Hydroxycitrate 2.2 (15) EthylLactate 15.0 (16) Niacinamide Salicylate 4.0 (17) Compound of formula(V) 1.1 (18) Paeonol 1.5 (19) Carnosine 0.1 (20) Cyclomethicone,Dimethicone Crosspolymer 2.0 (21) Arbutin 0.5 (22) Salicylic Acid 2.0(23) Polysorbate-202.0 (24) Polyacrylamide 2.0. Procedure. Mix (1) to(15) and heat at 70 to 80 C till homogenous. Cool to 40 to 50 C. Premix(16) to (23) and heat, if necessary, to a solution and add to main batchwith mixing. Cool to room temperature and add (24) and mix. An off-whitecream is obtained.

Example 8 Pet Cleanser

Ingredients. (1) PEG-647.229 (2) Hydroxypropyl Guar 0.4 (3) SodiumCocoyl Isethionate 20.0 (4) Sodium Lauryl Sulfoacetate 5.0 (5) BoswelliaSerrata 0.05 (6) L-Glutathione 0.01 (7) Resveratrol 0.01 (8) Compound offormula (VII) 1.1 (9) 2,6-Dihydroxy Acetophenone 0.001 (10) Ascorbicacid 10.0 (11) Phenoxyethanol 0.7 (12) Ethylhexylglycerin 0.3 (13)Fragrance 0.2 (14) Ethylhexyl Lactate 15.0. Procedure. Mix (1) and (2)to a clear thin gel. Add (3) and (4) and mix. Premix (5) to (14) to asolution. Add to main batch and mix. A white cream-like cleanser isobtained.

Example 9 Anti-Inflammatory Transparent Gel for Veterinary Use

Ingredients. (1) Ethyl Lactate 96.0 (2) Hydroxypropyl Guar 1.0 (3)Ximenia Oil 0.1 (4) N-(Deoxyaloesinylideneamino)-4-hydroxyphenylaceticacid (from Example 13) 1.0 (5) Magnolol (and) Honokiol 0.2 (6) Paeonol0.5 (7) Compound of formula (VII) 0.2 (8) Fragrance 1.0. Procedure. Mix(1) and (2) and heat at 50 to 60 C till clear. Cool to 40 to 45 C andadd all other ingredients and mix. Cool to room temperature. Atransparent gel-like product is obtained.

Example 10 Heat Releasing Face and Body Skin Brightening Cleanser

Ingredients. (1) Ethyl Lactate 5.0 (2) Hydroxypropyl Guar 0.4 (3)PEG-636.9 (4) Glycerin 2.0 (5) Vitamin E 0.1 (6) Botanicals blend 0.1(7) Zeolite 30.0 (8) Disodium Lauryl Sulfosuccinate powder 7.5 (9)Sodium Cocoyl Isethionate powder 11.0 (10) Shea butter 1.1 (11) ApricotKernel Oil 0.5 (12) Compound of formula (VIII) 1.1 (13) Mango butter 0.5(14) Fragrance 3.0 (15) Preservative 0.8. Procedure. Mix (1) to (3) andheat at 40 to 50 C till a clear gel is obtained (about one hour).Pre-mix (4) to (6) and add to main batch and mix. Add (7) to (13) andmix. Cool to 35 to 45 C. Add all other ingredients to main batch andmix. Cool to room temperature to an off-white paste. Upon application toslightly wet face or body, heat release is experienced and voluminousfoam is generated upon rubbing skin with some more water.

Example 11 Facial Glow Serum

Ingredients. (1) Butylene Glycol 57.9 (2) Water 10.0 (3) Ascorbic Acid10.0 (4) Diglycerol 10.0 (5) Bis-PEG-18 Methyl Ether Dimethyl Silane 4.0(6) Acrylates/Aminoacrylates/C-10-30 Alkyl PEG-20 Itaconate Copolymer4.0 (7) Compound of formula (VII) 1.5 (8) Glycine 1.0 (9) Magnolol 0.2(10) Baicalin 0.2 (11) Coleus Forskohlii Root Extract 0.1 (12)Preservative 1.0. Procedure. Make Premix A by mixing (2), (7), and (8)at 60 to 70 C for 30 min., then add (3) with mixing. Make Premix B bymixing all other ingredients, except (6), separately. Mix Premix A andPremix B, then add (6) with mixing to adjust viscosity.

Example 12 Facial Glow Cream

Ingredients. (1) Water 72.45 (2) Dicetyl phosphate and Ceteth-10phosphate 5.0 (3) Glyceryl Stearate and PEG-100 stearate 4.0 (4)Diglycerol 2.0 (5) Shea butter 2.0 (6) Aloesin 1.5 (7) Compound offormula (VII) 2.2 (8) Capuacu butter 1.0 (9) Sodium hydroxide 0.25 (10)Boswellia serrata extract 0.5 (11) Tetrahydrocurcumin 0.2 (12) Paeonol0.2 (13) Arbutin 1.1 (14) Coleus Forskohlii Root extract 0.1 (15)Polysorbate-204.0 (16) Carnosine 0.1 (17) Preservative 1.0 (18)Polyacrylamide and C13-14 Isoparaffin and Laureth-72.0. Procedure. MakePremix A by mixing (1), (6), and (7) at 80 to 90 C. Add all otheringredients and continue mixing until homogenous. Cool to roomtemperature.

Example 13 Dandruff Cleanser Shampoo

Ingredients. (1) Water 52.5 (2) Artemisia annua extract 1.5 (3) Glycine1.0 (4) Arbutin 0.5 (5) Magnolol 0.2 (6) Coleus Forskohlii Root Extract0.3 (7) Preservative 1.0 (8) Compound of formula (XII; R═H) 1.0 (9)Sodium Methyl Cocoyl Taurate 20.0 (10) Sodium Cocoyl Isethionate 20.0(11) PEG-120 Methyl Glucose Dioleate 2.0. Procedure. Mix (1) to (3) at80 to 90 C. Add all other ingredients. Continue mixing until homogenous.Cool to room temperature.

Example 14 High Foaming Pet Cleanser for Veterinary Use

Ingredients. (1) Water 51.4 (2) 1.5 (3) Zinc Salicylate Glycinate 2.1(4) Paeonol 0.5 (5) Magnolol 0.2 (6) Coleus Forskohlii Root Extract 0.3(7) Preservative 1.0 (8) Compound of formula (XII; R═H) 1.0 (9) SodiumMethyl Cocoyl Taurate 20.0 (10) Sodium Cocoyl Isethionate 20.0 (11)PEG-120 Methyl Glucose Dioleate 2.0. Procedure. Mix (1) to (11) at 80 to90 C. Continue mixing until homogenous. Cool to room temperature.

Example 15 Rosacea Cream

Ingredients. (1) Water 53.9 (2) Dicetyl Phosphate (and) Ceteth-10Phosphate 5.0 (3) Glyceryl Stearate (and) PEG-100 Stearate 4.0 (4)Phenoxyethanol 0.7 (5) Chlorphenesin 0.3 (60) Titanium Dioxide 0.2 (7)Sodium Hydroxide 0.5 (8) Magnolol 0.2 (9) Boswellia Serrata 0.5 (10)Cetyl Dimethicone 1.5 (11) Tetrahydrocurcuminoids 0.5 (12) Shea butter2.0 (13) Ximenia oil 1.0 (14) Niacinamide Hydroxycitrate 2.2 (15) EthylLactate 15.0 (16) Niacinamide Salicylate 4.0 (17) Artemisia annuaextract 10.1 (18) Paeonol 1.5 (19) Carnosine 0.1 (20) Cyclomethicone,Dimethicone Crosspolymer 2.0 (21) Compound of formula (XI; R═H) 0.5 (22)Salicylic Acid 2.0 (23) Polysorbate-202.0 (24) Polyacrylamide 2.0.Procedure. Mix (1) to (15) and heat at 70 to 80 C till homogenous. Coolto 40 to 50 C. Premix (16) to (23) and heat, if necessary, to a solutionand add to main batch with mixing. Cool to room temperature and add (24)and mix. An off-white cream is obtained.

Enzyme Inhibition Test.

A simple test to evaluate enzyme inhibition activity of the compounds ofthe present invention was done. A solution of compound from Example 1(0.1%) in warm water (to effect solubilization) was allowed to come incontact with a suspension of an enzyme in phosphate buffer and theinhibition was observed. The results are summarized in FIG. 2.

1. A compound of formula (I) or a salt thereof;

wherein, R¹, R², and R³ are selected from —OH, —NR⁴R⁵, amino sugar, and—OR⁶; and X is selected from —NH-peptide, —NH—C¹⁰—C²⁰ alkanoyl, and—N═CR⁷R⁸; and R⁴ and R⁵ are selected from H, alkyl, substituted alkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic,amino-alkanoyl, polyhydroxyalkyl, cycloalkyl, and amino sugar; and R⁶ isselected from H, and C¹-C²⁰ alkyl; and R⁷ and R⁸ are selected from H,alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, andsubstituted heterocyclic.
 2. (canceled)
 3. The compound of claim 1,wherein said compound is;


4. The compound of claim 1, wherein said compound is;


5. A composition comprising a compound of claim
 1. 6. A compositioncomprising said salt of a compound of claim 1, wherein said salt is ametal salt; said metal is selected from the group consisting of Li, Na,K, Ca, Mg, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn and Se.
 7. A compositioncomprising said salt of a compound of claim 1, wherein said salt is anacid salt; said acid is selected from the group consisting of inorganicand organic acids.
 8. A composition comprising a compound of claim 1 forpharmaceutical, nutraceutical, cosmetic, topical, or oral application.9. (canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled) 13.(canceled)
 14. The compound (I),

wherein; R¹ and R³ are selected from —OH, —NR⁴R⁵, amino sugar, and —OR⁶;and R² is —NHR⁹; and X is NH₂; and R⁴ and R⁵ are selected from H, alkyl,substituted alkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, amino-alkanoyl, polyhydroxyalkyl, cycloalkyl, and aminosugar; and R⁶ is selected from H, and C¹-C²⁰ alkyl; and Wand R⁸ areselected from H, alkyl, substituted alkyl, aryl, substituted aryl,heterocyclic, and substituted heterocyclic; and R⁹ is selected fromalkyl, substituted alkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, amino-alkanoyl, polyhydroxyalkyl, cycloalkyl,and amino sugar.
 15. A compound of claim 14, wherein said compound is;


16. A compound of claim 14, wherein said compound is;


17. A composition comprising a compound of claim
 14. 18. The compositionof claim 17, wherein said treatment is topical application. 19.(canceled)